rs397515626
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.62G>A(p.Arg21Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21W) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 11)
Exomes 𝑓: 0.0000041 ( 2 hom. )
Failed GnomAD Quality Control
Consequence
CRYAA
NM_000394.4 missense
NM_000394.4 missense
Scores
8
10
1
Clinical Significance
Conservation
PhyloP100: 7.25
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 chr21-43169160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
?
Variant 21-43169161-G-A is Pathogenic according to our data. Variant chr21-43169161-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43169161-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAA | NM_000394.4 | c.62G>A | p.Arg21Gln | missense_variant | 1/3 | ENST00000291554.6 | |
LOC107987300 | XR_007067885.1 | n.546+1876C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAA | ENST00000291554.6 | c.62G>A | p.Arg21Gln | missense_variant | 1/3 | 1 | NM_000394.4 | P1 | |
CRYAA | ENST00000482775.1 | n.75G>A | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 11
GnomAD3 genomes
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Cov.:
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251304Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135832
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 4AN: 972414Hom.: 2 Cov.: 21 AF XY: 0.00000408 AC XY: 2AN XY: 489658
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? Cov.: 11
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cataract 9 multiple types Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 21 of the CRYAA protein (p.Arg21Gln). This variant is present in population databases (rs397515626, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant early-onset cataracts (PMID: 23255486, 26867756). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68461). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg21 amino acid residue in CRYAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22045060, 22140512, 22347476, 23441109, 29386872). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 17, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
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
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at R21 (P = 0.2419);
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