chr2-208128258-C-T

Variant names:

• chr2-208128258-C-T
• rs398122392
• NM_020989.4:c.470G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_020989.4(CRYGC):​c.470G>A​(p.Trp157*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYGC NM_020989.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.52

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]

LOC100507443 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.105 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-208128258-C-T is Pathogenic according to our data. Variant chr2-208128258-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208128258-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGC	NM_020989.4	c.470G>A	p.Trp157*	stop_gained	Exon 3 of 3	ENST00000282141.4	NP_066269.1
LOC100507443	NR_038437.1	n.98-8798C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGC	ENST00000282141.4	c.470G>A	p.Trp157*	stop_gained	Exon 3 of 3	1	NM_020989.4	ENSP00000282141.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 2, multiple types Pathogenic:2

May 09, 2024

Miami Human Genetics, University Of Miami Miller School Of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Aug 26, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.470G>A (p.W157*) alteration, located in exon 3 (coding exon 3) of the CRYGC gene, consists of a G to A substitution at nucleotide position 470. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 157. This alteration occurs at the 3' terminus of the CRYGC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 10% of the protein. Premature stop codons are typically deleterious in nature, however, loss-of-function of CRYGC has not been established as a mechanism of disease. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in two individuals with features consistent with CRYGC-related cataract and found to segregate with affected individuals in one family (Zhang, 2009; Kessel, 2021). In an assay testing CRYGC function, this variant showed a functionally abnormal result (Talla, 2008). Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Nov 01, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The W157X variant in the CRYGC gene has been reported previously to segregate with autosomal dominant nuclear cataracts and mircrocornea in a four-generation Chinese family (Zhang et al., 2009). Functional studies with transfected W157X cells demonstrate self-aggregation and reduction in solubility that would be expected to generate light-scattering particles, compromising the transparency of the cells and their assemblies (Talla et. al, 2008). This variant is predicted to cause loss of normal protein function through protein truncation where the last 18 amino acid residues are lost. or nonsense-mediated mRNA decay. The W157X variant is not observed in large population cohorts (Lek et al., 2016). We interpret W157X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.71
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398122392; hg19: chr2-208992982;