rs11603779

chr11-111910323-A-Cchr11-111910323-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001289808.2(CRYAB):c.324+4T>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,724 control chromosomes in the GnomAD database, including 64,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5663 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59114 hom.)
• Consequence: CRYAB NM_001289808.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00003259
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.714

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039369464).
• BP6: Variant 11-111910323-A-C is Benign according to our data. Variant chr11-111910323-A-C is described in ClinVar as [Benign]. Clinvar id is 44234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-111910323-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAB	NM_001289808.2	c.324+4T>G		splice_donor_region_variant, intron_variant		ENST00000650687.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAB	ENST00000650687.2	c.324+4T>G		splice_donor_region_variant, intron_variant			NM_001289808.2	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40773 AN: 151948 Hom.: 5665 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.274 AC: 68923 AN: 251388 Hom.: 9761 AF XY: 0.277 AC XY: 37647 AN XY: 135876

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.282 AC: 412753 AN: 1461658 Hom.: 59114 Cov.: 36 AF XY: 0.282 AC XY: 205345 AN XY: 727140

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.358

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.248

Gnomad4 NFE exome AF: 0.288

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.268 AC: 40778 AN: 152066 Hom.: 5663 Cov.: 32 AF XY: 0.268 AC XY: 19914 AN XY: 74334

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.301

Alfa AF: 0.282 Hom.: 6697

Bravo AF: 0.271

TwinsUK AF: 0.289 AC: 1070

ALSPAC AF: 0.303 AC: 1169

ESP6500AA AF: 0.219 AC: 962

ESP6500EA AF: 0.300 AC: 2578

ExAC AF: 0.270 AC: 32718

Asia WGS AF: 0.229 AC: 796 AN: 3478

EpiCase AF: 0.311

EpiControl AF: 0.302

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Fatal infantile hypertonic myofibrillar myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Cataract 16 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Myofibrillar myopathy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Dilated cardiomyopathy 1II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Myofibrillar Myopathy, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	1.1
Dann	Benign	0.51
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PROVEAN	Benign	2.1	N
REVEL	Benign	0.15
Sift	Benign	0.43	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.16
ClinPred		0.0037	T
GERP RS		-6.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs11603779; hg19: chr11-111781047; COSMIC: COSV57051476; COSMIC: COSV57051476;