2-208124255-G-T

Variant names:

• chr2-208124255-G-T
• rs121909597
• NM_006891.4:c.109C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_006891.4(CRYGD):​c.109C>A​(p.Arg37Ser) variant causes a missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYGD NM_006891.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.69

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 12 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 chr2-208124254-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-208124255-G-T is Pathogenic according to our data. Variant chr2-208124255-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 16939.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-208124255-G-T is described in UniProt as null. Variant chr2-208124255-G-T is described in Lovd as [Likely_pathogenic]. Variant chr2-208124255-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGD	NM_006891.4	c.109C>A	p.Arg37Ser	missense_variant	Exon 2 of 3	ENST00000264376.5	NP_008822.2
LOC100507443	NR_038437.1	n.97+5030G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5	c.109C>A	p.Arg37Ser	missense_variant	Exon 2 of 3	1	NM_006891.4	ENSP00000264376.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000896 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 4 multiple types Pathogenic:1

Sep 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aculeiform cataract Pathogenic:1

Mar 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 37 of the CRYGD protein (p.Arg37Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital cataracts (PMID: 10915766, 22219628; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as R36S. ClinVar contains an entry for this variant (Variation ID: 16939). 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. This variant disrupts the p.Arg37Pro amino acid residue in CRYGD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21527994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.27	N
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.89		Loss of stability (P = 0.0838);
MVP		0.88
MPC		0.56
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.97
gMVP		0.81

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: rs121909597; hg19: chr2-208988979;