rs104893618
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_020989.4(CRYGC):c.13A>C(p.Thr5Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CRYGC
NM_020989.4 missense
NM_020989.4 missense
Scores
9
7
2
Clinical Significance
Conservation
PhyloP100: 4.96
Genes affected
CRYGC (HGNC:2410): (crystallin gamma C) This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute the major proteins of vertebrate eye lens and maintain the transparency and refractive index of the lens. This gene and several family members are present in a gene cluster on chromosome 2. Mutations in this gene have been shown to cause multiple types of cataract, including Coppock-like cataract and zonular pulverulent cataract, among others. [provided by RefSeq, Jan 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
?
In a domain Beta/gamma crystallin 'Greek key' 1 (size 38) in uniprot entity CRGC_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_020989.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 2-208129680-T-G is Pathogenic according to our data. Variant chr2-208129680-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 16943.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-208129680-T-G is described in UniProt as null. Variant chr2-208129680-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRYGC | NM_020989.4 | c.13A>C | p.Thr5Pro | missense_variant | 2/3 | ENST00000282141.4 | |
LOC100507443 | NR_038437.1 | n.98-7376T>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRYGC | ENST00000282141.4 | c.13A>C | p.Thr5Pro | missense_variant | 2/3 | 1 | NM_020989.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 exome
AF:
AC:
1
AN:
1461894
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727248
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cataract 2, Coppock-like Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2003 | - - |
Nuclear pulverulent cataract Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2023 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 5 of the CRYGC protein (p.Thr5Pro). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CRYGC function (PMID: 12601044). 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: 16943). This variant is also known as 225A>C. This missense change has been observed in individual(s) with congenital cataract (PMID: 10521291, 33243271). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
T
Polyphen
D
Vest4
MutPred
Loss of phosphorylation at T5 (P = 0.0777);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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