rs150516929
Positions:
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2
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
NM_001289808.2 missense
Scores
1
4
14
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -10 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).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000847 (129/152252) while in subpopulation NFE AF= 0.00165 (112/68010). AF 95% confidence interval is 0.0014. There are 2 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 129 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CRYAB | NM_001289808.2 | c.460G>A | p.Gly154Ser | missense_variant | 3/3 | ENST00000650687.2 | NP_001276737.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CRYAB | ENST00000650687.2 | c.460G>A | p.Gly154Ser | missense_variant | 3/3 | NM_001289808.2 | ENSP00000499082.1 |
Frequencies
GnomAD3 genomes 0.000848 AC: 129AN: 152134Hom.: 2 Cov.: 32
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GnomAD3 exomes AF: 0.000907 AC: 228AN: 251488Hom.: 0 AF XY: 0.000787 AC XY: 107AN XY: 135918
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GnomAD4 exome AF: 0.00122 AC: 1784AN: 1461590Hom.: 1 Cov.: 31 AF XY: 0.00116 AC XY: 847AN XY: 727108
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GnomAD4 genome 0.000847 AC: 129AN: 152252Hom.: 2 Cov.: 32 AF XY: 0.000833 AC XY: 62AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:7Benign:16
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:6
| Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 12, 2021 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 22, 2022 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Mar 31, 2017 | 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 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 01, 2014 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | CRYAB: BP4 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 05, 2024 | 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:1Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 11, 2015 | 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. - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 30, 2024 | - - |
Dilated cardiomyopathy 1II Pathogenic:1Benign:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 11, 2006 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 27, 2014 | - - |
Developmental cataract Uncertain:1
| Uncertain significance, no assertion criteria provided | research | Eye Genetics Research Group, Children's Medical Research Institute | Jan 09, 2015 | - - |
Hypertrophic cardiomyopathy;C0018802:Congestive heart failure Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Apr 09, 2019 | - - |
Myofibrillar Myopathy, Dominant Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiomyopathy Benign:1
| Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 16, 2018 | - - |
CRYAB-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 10, 2021 | 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
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 20, 2019 | 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
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T;T;T;T;T;T;T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;.;T;.;.;.;.;T;.;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;N;N;N;N;N;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;.;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;.;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;.;.;.
Polyphen
B;.;.;B;B;B;B;B;.;.;.
Vest4
MVP
MPC
0.38
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at