rs74315441
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PP3_StrongPP5_Moderate
The NM_000394.4(CRYAA):c.145C>T(p.Arg49Cys) variant causes a missense change involving the alteration of a non-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. R49H) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 9)
Exomes 𝑓: 0.0000026 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CRYAA
NM_000394.4 missense
NM_000394.4 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 1.68
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 Likely_pathogenic. Variant got 8 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
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
?
Variant 21-43169244-C-T is Pathogenic according to our data. Variant chr21-43169244-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16959.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-43169244-C-T is described in Lovd as [Pathogenic]. Variant chr21-43169244-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYAA | NM_000394.4 | c.145C>T | p.Arg49Cys | missense_variant | 1/3 | ENST00000291554.6 | |
LOC107987300 | XR_007067885.1 | n.546+1793G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYAA | ENST00000291554.6 | c.145C>T | p.Arg49Cys | missense_variant | 1/3 | 1 | NM_000394.4 | P1 | |
CRYAA | ENST00000482775.1 | n.158C>T | non_coding_transcript_exon_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 2AN: 76940Hom.: 0 Cov.: 9 FAILED QC
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249112Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134862
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000259 AC: 2AN: 772640Hom.: 0 Cov.: 10 AF XY: 0.00000250 AC XY: 1AN XY: 400204
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000260 AC: 2AN: 76940Hom.: 0 Cov.: 9 AF XY: 0.0000541 AC XY: 2AN XY: 36992
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cataract 9 multiple types Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | This missense change has been observed in individual(s) with autosomal dominant CRYAA-related conditions (PMID: 14512969). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CRYAA function (PMID: 14512969, 18056999, 22140512). 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. ClinVar contains an entry for this variant (Variation ID: 16959). This variant is present in population databases (rs74315441, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 49 of the CRYAA protein (p.Arg49Cys). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2003 | - - |
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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
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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