11-111908768-T-A
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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
NM_001289808.2 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 4.68
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 |
---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.524A>T | p.Lys175Ile | missense_variant | 3/3 | ENST00000650687.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.524A>T | p.Lys175Ile | missense_variant | 3/3 | NM_001289808.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460332Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726488
GnomAD4 exome
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3
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1460332
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31
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0
AN XY:
726488
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
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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 submitter | clinical testing | Invitae | Aug 31, 2021 | This 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T;T;T;T;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;.;T;.;.;.;.;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;M;M;M;M;M;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;D;D;.;N;N;N;N;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;.;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;.
Polyphen
B;.;.;B;B;B;B;B;.
Vest4
MutPred
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
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at