11-111911664-TGG-TG
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_001289808.2(CRYAB):c.60delC(p.Ser21AlafsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P20P) has been classified as Benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CRYAB
NM_001289808.2 frameshift
NM_001289808.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.620
Publications
10 publications found
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 Gene-Disease associations (from GenCC):
- myofibrillar myopathy 2Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
- cataract 16 multiple typesInheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
- fatal infantile hypertonic myofibrillar myopathyInheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
- early-onset lamellar cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset nuclear cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- early-onset posterior polar cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy 1IIInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-111911664-TG-T is Pathogenic according to our data. Variant chr11-111911664-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29669.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CRYAB | NM_001289808.2 | c.60delC | p.Ser21AlafsTer24 | frameshift_variant | Exon 1 of 3 | ENST00000650687.2 | NP_001276737.1 | |
| CRYAB | NM_001289807.1 | c.60delC | p.Ser21AlafsTer24 | frameshift_variant | Exon 2 of 4 | NP_001276736.1 | ||
| CRYAB | NM_001368245.1 | c.60delC | p.Ser21AlafsTer24 | frameshift_variant | Exon 2 of 4 | NP_001355174.1 | ||
| CRYAB | NM_001885.3 | c.60delC | p.Ser21AlafsTer24 | frameshift_variant | Exon 2 of 4 | NP_001876.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1456450Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 723764
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1456450
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
723764
African (AFR)
AF:
AC:
0
AN:
33446
American (AMR)
AF:
AC:
0
AN:
43746
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25932
East Asian (EAS)
AF:
AC:
0
AN:
39562
South Asian (SAS)
AF:
AC:
0
AN:
85020
European-Finnish (FIN)
AF:
AC:
0
AN:
52984
Middle Eastern (MID)
AF:
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1109772
Other (OTH)
AF:
AC:
0
AN:
60226
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Myofibrillar myopathy 2 Pathogenic:1Other:1
May 01, 2011
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
- -
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only
- -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
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
Publications
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