rs11603779

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001289808.2(CRYAB):c.324+4T>G variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron

Scores

Splicing: ADA: 0.00003259

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.714

Variant links:

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]

CRYAB links:

CRYAB (HGNC:):

CRYAB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CRYAB	NM_001289808.2 linkuse as main transcript	c.324+4T>G		splice_region_variant, intron_variant		ENST00000650687.2	NP_001276737.1	P02511V9HW27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 linkuse as main transcript	c.324+4T>G		splice_region_variant, intron_variant			NM_001289808.2	ENSP00000499082.1		P02511

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40773

AN:

151948

Hom.:

5665

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.282

AC XY:

205345

AN XY:

727140

show subpopulations

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.:

AF XY:

0.268

AC XY:

19914

AN XY:

74334

show subpopulations

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:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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	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	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Myofibrillar Myopathy, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.46

CADD

Benign

1.1

DANN

Benign

0.51

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

PROVEAN

Benign

2.1

REVEL

Benign

0.15

Sift

Benign

0.43

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.16

ClinPred

0.0037

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over