2-208121780-G-A

Variant names:

• chr2-208121780-G-A
• rs1337897299
• NM_006891.4:c.418C>T

Variant summary

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

The NM_006891.4(CRYGD):​c.418C>T​(p.Arg140*) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYGD NM_006891.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.0100

Genes affected

CRYGD (HGNC:2411): (crystallin gamma D) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are tandemly organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

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. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-208121780-G-A is Pathogenic according to our data. Variant chr2-208121780-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 574060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208121780-G-A is described in Lovd as [Pathogenic]. Variant chr2-208121780-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-208121780-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGD	NM_006891.4	c.418C>T	p.Arg140*	stop_gained	Exon 3 of 3	ENST00000264376.5	NP_008822.2
LOC100507443	NR_038437.1	n.97+2555G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5	c.418C>T	p.Arg140*	stop_gained	Exon 3 of 3	1	NM_006891.4	ENSP00000264376.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 4 multiple types Pathogenic:2

Mar 09, 2021

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 31, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418C>T (p.R140*) alteration, located in exon 3 (coding exon 3) of the CRYGD gene, consists of a C to T substitution at nucleotide position 418. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 140. This alteration occurs at the 3' terminus of the CRYGD gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 20% of the protein. The exact functional effect of this alteration is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with congenital or juvenile-onset cataracts and has been shown to cosegregate with disease in multiple families (Devi, 2008; Reis, 2013; Zhai, 2014; Li, 2018; Berry, 2020; Jackson, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

CRYGD-related disorder Pathogenic:1

Apr 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CRYGD c.418C>T variant is predicted to result in premature protein termination (p.Arg140*). This variant occurs within the terminal exon of the CRYGD gene and truncates the coding sequence by 34 amino acids. This variant was reported in individuals with pediatric cataract and segregation was observed in multiple families (Devi et al. 2008. PubMed ID: 18587492; Berry et al. 2020. PubMed ID: 33243271; Reis et al. 2013. PubMed ID: 23508780; Zhai et al. 2014. PubMed ID: 24465161). Functional studies showed that this variant disrupts the c-terminal Greek key motif, causing lowered solubility and perturbing protein structure (Vendra et al. 2013. PubMed ID: 23936409). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CRYGD are expected to be pathogenic. This variant is interpreted as pathogenic. -

Aculeiform cataract Pathogenic:1

Jan 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CRYGD function (PMID: 23936409). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 574060). This sequence change creates a premature translational stop signal (p.Arg140*) in the CRYGD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the CRYGD protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with nonsyndromic congenital cataracts (PMID: 18587492, 2350878024465161). It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
Vest4		0.79
GERP RS		-2.3

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: rs1337897299; hg19: chr2-208986504; COSMIC: COSV52206102;