rs397516686
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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
NM_001289808.2 start_lost
Scores
6
6
4
Clinical Significance
Conservation
PhyloP100: 7.67
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 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 | c.3G>A | p.Met1? | start_lost | 1/3 | ENST00000650687.2 | NP_001276737.1 | |
CRYAB | NM_001289807.1 | c.3G>A | p.Met1? | start_lost | 2/4 | NP_001276736.1 | ||
CRYAB | NM_001368245.1 | c.3G>A | p.Met1? | start_lost | 2/4 | NP_001355174.1 | ||
CRYAB | NM_001885.3 | c.3G>A | p.Met1? | start_lost | 2/4 | NP_001876.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CRYAB | ENST00000650687.2 | c.3G>A | p.Met1? | start_lost | 1/3 | NM_001289808.2 | ENSP00000499082.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152100Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000674 AC: 13AN: 192938Hom.: 1 AF XY: 0.0000484 AC XY: 5AN XY: 103220
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GnomAD4 exome AF: 0.0000147 AC: 21AN: 1429202Hom.: 1 Cov.: 30 AF XY: 0.0000127 AC XY: 9AN XY: 707398
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74310
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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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
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
LIST_S2
Uncertain
.;D;.;.;.;.;.;D;D;D;.
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
PROVEAN
Benign
N;.;N;N;N;N;N;N;N;D;N
REVEL
Pathogenic
Sift
Benign
T;.;T;T;T;T;T;T;T;D;D
Sift4G
Benign
T;T;T;T;T;T;.;.;T;.;.
Polyphen
D;D;D;D;D;D;.;.;D;.;.
Vest4
MutPred
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
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at