rs281865142

Positions:

chr11-111908948-GA-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PVS1_StrongPP5BS2

The NM_001289808.2(CRYAB):c.343del(p.Ser115ProfsTer14) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000991 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CRYAB
NM_001289808.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 5.29

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PP5

Variant 11-111908948-GA-G is Pathogenic according to our data. Variant chr11-111908948-GA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38963.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1, Pathogenic=4}.

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYAB	NM_001289808.2 linkuse as main transcript	c.343del	p.Ser115ProfsTer14	frameshift_variant	3/3	ENST00000650687.2	NP_001276737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 linkuse as main transcript	c.343del	p.Ser115ProfsTer14	frameshift_variant	3/3		NM_001289808.2	ENSP00000499082	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250916

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 61 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect as induced pluripotent stem cells (iPSC) derived from fibroblasts from an infant with myofibrillar myopathy showed that this variant causes protein insolubility, resulting in the loss of alpha-B-crystallin protein expression in iPSC-derived skeletal myotubes and cardiomyocytes (Mitzelfelt et al., 2016); Reported in ClinVar (ClinVar Variant ID# 38963; Landrum et al., 2016); While other truncating variants in the CRYAB gene have been reported in HGMD in association with autosomal recessive infantile myofibrillar myopathy (Stenson et al., 2014), only one truncating variant has been previously reported in association with autosomal dominant cardiomyopathy (Jensen et al. 2013).; This variant is associated with the following publications: (PMID: 21130652, 27226619, 31534214) -

Dilated cardiomyopathy 1II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

This sequence change creates a premature translational stop signal (p.Ser115Profs*14) in the CRYAB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the CRYAB protein. This variant is present in population databases (rs281865142, gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive myofibrillar myopathy (PMID: 21130652, 27226619). ClinVar contains an entry for this variant (Variation ID: 38963). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CRYAB function (PMID: 21130652, 27226619). For these reasons, this variant has been classified as Pathogenic. -

Myofibrillar myopathy 2;C3554649:Dilated cardiomyopathy 1II;C3808377:Cataract 16 multiple types;C5190691:Fatal infantile hypertonic myofibrillar myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 27, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.343delT (p.S115Pfs*14) alteration, located in exon 3 (coding exon 3) of the CRYAB gene, consists of a deletion of one nucleotide at position 343, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 2

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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