rs397515624
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000394.4(CRYAA):c.34C>T(p.Arg12Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 11)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CRYAA
NM_000394.4 missense
NM_000394.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 5.49
Genes affected
CRYAA (HGNC:2388): (crystallin alpha A) 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. Post-translational modifications decrease the ability to chaperone. 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. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a chain Alpha-crystallin A(1-168) (size 167) in uniprot entity CRYAA_HUMAN there are 43 pathogenic changes around while only 1 benign (98%) in NM_000394.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
?
Variant 21-43169133-C-T is Pathogenic according to our data. Variant chr21-43169133-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43169133-C-T is described in Lovd as [Pathogenic]. Variant chr21-43169133-C-T is described in Lovd as [Pathogenic]. Variant chr21-43169133-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAA | NM_000394.4 | c.34C>T | p.Arg12Cys | missense_variant | 1/3 | ENST00000291554.6 | |
LOC107987300 | XR_007067885.1 | n.546+1904G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAA | ENST00000291554.6 | c.34C>T | p.Arg12Cys | missense_variant | 1/3 | 1 | NM_000394.4 | P1 | |
CRYAA | ENST00000482775.1 | n.47C>T | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 11
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251338Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
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GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 961744Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 482826
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Data not reliable, filtered out with message: AC0;AS_VQSR
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GnomAD4 genome ? Cov.: 11
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cataract 9 multiple types Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CRYAA protein function (PMID: 22140512, 22347476). This variant has been observed in individuals with autosomal dominant congenital cataracts (PMID: 17724170, 19503744, 22045060, 23508780) and segregates with disease in families (PMID: 19503744, 23508780). ClinVar contains an entry for this variant (Variation ID: 68459). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 12 of the CRYAA protein (p.Arg12Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jul 28, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 29, 2021 | - - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Abnormality of the eye Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Cataract 9, multiple types, with microcornea Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
Developmental cataract Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania | May 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at R12 (P = 0.011);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at