rs150516929

Variant names:

• chr11-111908832-C-T
• rs150516929
• NM_001289808.2:c.460G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001289808.2(CRYAB):​c.460G>A​(p.Gly154Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00119 in 1,613,842 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CRYAB NM_001289808.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:16
• Conservation: PhyloP100: 3.74

Genes affected

CRYAB (HGNC:2389): (crystallin alpha B) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a domain sHSP (size 108) in uniprot entity CRYAB_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001289808.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.043476284).
• BS2: High AC in GnomAd4 at 129 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAB	NM_001289808.2	c.460G>A	p.Gly154Ser	missense_variant	Exon 3 of 3	ENST00000650687.2	NP_001276737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2	c.460G>A	p.Gly154Ser	missense_variant	Exon 3 of 3		NM_001289808.2	ENSP00000499082.1

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000907 AC: 228 AN: 251488 Hom.: 0 AF XY: 0.000787 AC XY: 107 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00122 AC: 1784 AN: 1461590 Hom.: 1 Cov.: 31 AF XY: 0.00116 AC XY: 847 AN XY: 727108

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74444

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00135 Hom.: 2

Bravo AF: 0.000691

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00136

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:6

Dec 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CRYAB: BP4 -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Given the high prevalence of this variant in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been reported multiple times in the literature associated with dilated cardiomyopathy, myofibrillar myopathy and cataracts. However, recently published control population data indicates that this variant is common in healthy people (MAF 0.15%) and so was likely found by chance in these reports. The variant has been seen in at least 21 unrelated cases of dilated cardiomyopathy, myofibrillar myopathy and cataracts (not including this patient's family). There is little segregation data, which is weak. At least 5 of the 17 probands sequenced at clinical labs had another pathogenic or likely pathogenic variant in another gene. This variant is present in ClinVar, with conflicting interpretations of pathogenicity. Emory and GeneDx classify this as a variant of uncertain significance. The Laboratory for Molecular Medicine classifies this as a variant of uncertain significance, likely benign. The Illumina Clinical Services Laboratory classifies it as likely benign. This variant was identified in a 48 year old patient with DCM. Had a father with heart failure dx at 60 and died at 80. Paternal history of ocular problems, not otherwise specified (Pilotto et al 2006). This variant was found in a 70 year old male patient with distal myopathy, with onset at 60 years. The patient's maternal grandmother also had a cardiomyopathy. The patient also had coronary artery disease and intermittent atrial fibrillation. ECG showed right bundle branch block and echocardiogram showed a dilated right atrium. No eye findings other than very mild, age-appropriate cataracts. Sequencing of other genes associated with myofibrillar myopathy was negative: DES, TTID, LDB3 and FLNC (Reilich et al 2010). Vattemi and colleagues (2011) found this variant in 1 out of 21 patients with myofibrillar myopathy. Semmler and colleagues (2014) found this variant in a patient who presented at 69 years of age with several episodes of rhabdomyolitis, exercise intolerance, fatigue and respiratory insufficiency. His 42 year old son also had this variant and did not have any symptoms except for a mild elevation in CK. In terms of functional data, Raju et al demonstrated that HeLa cells transfected with this variant showed a moderate amount of aggregation, a phenomenon common in myofibrillar myopathy. Huang et al 2016 found that the G154S variant did not affect beta-crystallin's capability in enhancing the sodium current density. According to the test report, "the G154S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties." The glycine at codon 154 is moderately conserved across species, as are neighboring amino acids. The variant was reported online in 223 of 123,132 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 169 of 55,857 individuals of European (non-Finnish) descent (MAF=0.15%), 31 out of 11,150 individuals of Finnish descent, 17 out of 16,791 individuals of Latino descent, 4 out of 2,743 individuals of "other" descent, 1 out of 7,652 individuals of African descent and 1 out of 4,925 individuals of Ashkenazi Jewish descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencie -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with both DCM, myopathy, and sudden cardiac death (SCD) (PMID: 16793013, 20171888, 22106715, 25208129, 26694549, 35087879); Functional studies suggest the presence of this variant may alter protein interactions under various experimental conditions; however, it is not known whether these findings are biological or clinically relevant in vivo (PMID: 23194663, 26961874, 28919577, 34983005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21920752, 27896284, 22995991, 23299917, 22106715, 26210153, 26961874, 24694370, 26694549, 20171888, 25961584, 21423662, 28518168, 28919577, 32171521, 32955210, 30325262, 29915098, 37511242, 25208129, 16793013, 23194663, 34983005, 35087879) -

not specified Uncertain:1 Benign:2

Mar 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Gly154Ser var iant in CRYAB has been reported in 2 individuals with mild DCM (Inagaki 2006, Pi lotto 2006) and in 2 individuals with myopathy (Reilich 2010, Semmler 2014). Add itionally, one unpublished study detected this variant in 8 individuals with HCM (Sriram 2007; conference abstract). This variant has also been identified by ou r laboratory in 3 individuals with HCM, 2 individuals with DCM, and 1 individual with RV dilation and ventricular tachycardia. However, one of the individuals w ith HCM carried a variant in another gene that is sufficient to explain their di sease. This variant has been identified in 0.1% (85/66736) of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs150516929). In vitro functional studies provide some evidence that the p.G ly154Ser variant may impact protein function (Inagaki 2006, Reilich 2010, Ragu 2 013). However, these types of assays may not accurately represent biological fun ction. In summary, while the clinical significance of the p.Gly154Ser variant is uncertain, the wide range of phenotypes of individuals with this variant and it s frequency in the general population suggest that it is more likely to be benig n. -

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Dilated cardiomyopathy 1II Pathogenic:1 Benign:1

Aug 11, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Primary familial hypertrophic cardiomyopathy Uncertain:1

Oct 27, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Developmental cataract Uncertain:1

Jan 09, 2015

Eye Genetics Research Group, Children's Medical Research Institute

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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Hypertrophic cardiomyopathy;C0018802:Congestive heart failure Benign:1

Apr 09, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Myofibrillar Myopathy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Cardiomyopathy Benign:1

Mar 16, 2018

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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CRYAB-related disorder Benign:1

May 10, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Fatal infantile hypertonic myofibrillar myopathy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Mar 20, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cataract 16 multiple types Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;.
Eigen	Benign	0.094
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	.;.;.;T;.;.;.;.;T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.043	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.65	N;.;.;N;N;N;N;N;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.19	N;N;N;.;N;N;N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.44	T;T;T;.;T;T;T;T;T;T;T
Sift4G	Benign	0.81	T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.025	B;.;.;B;B;B;B;B;.;.;.
Vest4		0.60
MVP		0.99
MPC		0.38
ClinPred		0.020	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150516929; hg19: chr11-111779556;