rs121909595

Positions:

• chr2-208124321-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006891.4(CRYGD):​c.43C>T​(p.Arg15Cys) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYGD NM_006891.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.58

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 18 ACMG points.

• PM1: In a domain Beta/gamma crystallin 'Greek key' 1 (size 38) in uniprot entity CRGD_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_006891.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-208124321-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 2-208124321-G-A is Pathogenic according to our data. Variant chr2-208124321-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208124321-G-A is described in UniProt as null. Variant chr2-208124321-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGD	NM_006891.4	c.43C>T	p.Arg15Cys	missense_variant	2/3	ENST00000264376.5	NP_008822.2
LOC100507443	NR_038437.1	n.97+5096G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5	c.43C>T	p.Arg15Cys	missense_variant	2/3	1	NM_006891.4	ENSP00000264376	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 4 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2023

Published functional studies demonstrate a damaging effect (Pande et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); This variant has been reported in the published literature using alternate nomenclature R14C; This variant is associated with the following publications: (PMID: 19382745, 19007775, 20577655, 29652984, 18035564, 26732753, 32899552, 21423869, 24384146, 29222017, 10688888, 23954869, 34150533, 19668596, 24465161, 20508808, 16446699, 32148946, 9927684) -

Aculeiform cataract Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2021

This variant disrupts the p.Arg15 amino acid residue in CRYGD. Other variant(s) that disrupt this residue have been observed in individuals with CRYGD-related conditions (PMID: 19668596, 28450710), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This sequence change replaces arginine with cysteine at codon 15 of the CRYGD protein (p.Arg15Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with congenital and juvenile onset cataract in families (PMID: 16446699, 9927684 ). This variant is also known as c.34C>T, p.R14C in the literature. ClinVar contains an entry for this variant (Variation ID: 16937). This variant has been reported to affect the CRYGD protein function (PMID: 19382745, 10688888 ). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.010	D
Polyphen		0.94	P
Vest4		0.48
MutPred		0.92		Loss of disorder (P = 0.0116);
MVP		0.91
MPC		1.0
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.69
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909595; hg19: chr2-208989045;