11-111911609-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001289808.2(CRYAB):c.116C>A(p.Pro39Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
CRYAB
NM_001289808.2 missense
NM_001289808.2 missense
Scores
4
10
4
Clinical Significance
Conservation
PhyloP100: 6.14
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 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.819
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAB | NM_001289808.2 | c.116C>A | p.Pro39Gln | missense_variant | 1/3 | ENST00000650687.2 | |
CRYAB | NM_001289807.1 | c.116C>A | p.Pro39Gln | missense_variant | 2/4 | ||
CRYAB | NM_001368245.1 | c.116C>A | p.Pro39Gln | missense_variant | 2/4 | ||
CRYAB | NM_001885.3 | c.116C>A | p.Pro39Gln | missense_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.116C>A | p.Pro39Gln | missense_variant | 1/3 | NM_001289808.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
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 | Jun 28, 2018 | This variant has not been reported in the literature in individuals with CRYAB-related disease. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with glutamine at codon 39 of the CRYAB protein (p.Pro39Gln). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and glutamine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D;D;T;T;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;D;D;D;T;T;D;D
Sift4G
Benign
T;T;T;T;T;T;.;.;D;.;.
Polyphen
D;D;D;D;D;D;.;.;D;.;.
Vest4
MutPred
Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);Loss of glycosylation at T40 (P = 0.0501);
MVP
MPC
0.88
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