rs397516686

Positions:

chr11-111911722-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_001289808.2(CRYAB):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,581,302 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

CRYAB
NM_001289808.2 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 7.67

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 Uncertain_significance. Variant got 5 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PP5

Variant 11-111911722-C-T is Pathogenic according to our data. Variant chr11-111911722-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44236.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=1}.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYAB	NM_001289808.2 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/3	ENST00000650687.2	NP_001276737.1	P02511V9HW27
CRYAB	NM_001289807.1 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4		NP_001276736.1	P02511V9HW27
CRYAB	NM_001368245.1 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4		NP_001355174.1
CRYAB	NM_001885.3 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	2/4		NP_001876.1	P02511V9HW27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/3		NM_001289808.2	ENSP00000499082.1		P02511

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

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:

0.0000674

AC:

AN:

192938

Hom.:

AF XY:

0.0000484

AC XY:

AN XY:

103220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000884

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1429202

Hom.:

Cov.:

AF XY:

0.0000127

AC XY:

AN XY:

707398

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000545

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000770

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000498

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2021	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31215171, 33834702) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 24, 2021	- -

Dilated cardiomyopathy 1II

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change affects the initiator methionine of the CRYAB mRNA. The next in-frame methionine is located at codon 68. This variant is present in population databases (rs397516686, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. Disruption of the initiator codon has been observed in individuals with autosomal recessive myofibrillar myopathy (PMID: 31215171, 33834702). ClinVar contains an entry for this variant (Variation ID: 44236). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 13, 2012

The Met1? variant (CRYAB) has not been reported in the literature and has not be en previously detected by our laboratory. This variant is predicted to severely affect the synthesis of the CRYAB protein by disrupting the translation initiat ion start codon (ATG). In summary, this variant is likely to be pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D;D;D;D;D;T;T;T;T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;.;.;.;.;.;D;D;D;.

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.70

PROVEAN

Benign

-2.2

N;.;N;N;N;N;N;N;N;D;N

REVEL

Pathogenic

0.82

Sift

Benign

0.096

T;.;T;T;T;T;T;T;T;D;D

Sift4G

Benign

0.17

T;T;T;T;T;T;.;.;T;.;.

Polyphen

1.0

D;D;D;D;D;D;.;.;D;.;.

Vest4

0.82

MutPred

0.74

Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);Gain of catalytic residue at M1 (P = 0.0245);

MVP

0.96

ClinPred

0.68

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.87

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

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