11-111908768-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001289808.2(CRYAB):​c.524A>T​(p.Lys175Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CRYAB
NM_001289808.2 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CRYABNM_001289808.2 linkuse as main transcriptc.524A>T p.Lys175Ile missense_variant 3/3 ENST00000650687.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CRYABENST00000650687.2 linkuse as main transcriptc.524A>T p.Lys175Ile missense_variant 3/3 NM_001289808.2 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460332
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726488
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1II Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 31, 2021This sequence change replaces lysine with isoleucine at codon 175 of the CRYAB protein (p.Lys175Ile). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CRYAB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.37
T;T;T;T;T;T;T;T;T
Eigen
Benign
0.11
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.80
.;.;.;T;.;.;.;.;T
M_CAP
Uncertain
0.23
D
MetaRNN
Uncertain
0.47
T;T;T;T;T;T;T;T;D
MetaSVM
Uncertain
0.58
D
MutationAssessor
Uncertain
2.2
M;.;.;M;M;M;M;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-2.2
N;D;D;.;N;N;N;N;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0010
D;D;D;.;D;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D;D;D;D;.
Polyphen
0.13
B;.;.;B;B;B;B;B;.
Vest4
0.60
MutPred
0.34
Gain of stability (P = 0.0023);.;.;Gain of stability (P = 0.0023);Gain of stability (P = 0.0023);Gain of stability (P = 0.0023);Gain of stability (P = 0.0023);Gain of stability (P = 0.0023);.;
MVP
0.78
MPC
1.0
ClinPred
0.98
D
GERP RS
4.8
Varity_R
0.76
gMVP
0.45

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.

Other links and lift over

dbSNP: rs1965351856; hg19: chr11-111779492; API