rs121909596

chr2-208124188-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_006891.4(CRYGD):c.176G>A(p.Arg59His) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYGD NM_006891.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: -0.139

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 2-208124188-C-T is Pathogenic according to our data. Variant chr2-208124188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16938.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr2-208124188-C-T is described in UniProt as null. Variant chr2-208124188-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYGD	NM_006891.4	c.176G>A	p.Arg59His	missense_variant	2/3	ENST00000264376.5
LOC100507443	NR_038437.1	n.97+4963C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYGD	ENST00000264376.5	c.176G>A	p.Arg59His	missense_variant	2/3	1	NM_006891.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 4 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Aculeiform cataract Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 07, 2017

This sequence change replaces arginine with histidine at codon 59 of the CRYGD protein (p.Arg59His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. In summary, this is a rare missense change that has been reported to segregate with disease in multiple families. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been reported to segregate with the aculeiform-cataract phenotype in several families (PMID: 10521291). This variant is also known as c.411G>A, p.R58H in the literature. ClinVar contains an entry for this variant (Variation ID: 16938). This variant is not present in population databases (ExAC no frequency). -

CRYGD-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

The CRYGD c.176G>A variant is predicted to result in the amino acid substitution p.Arg59His. In the literature, this variant is also referred to as c.411G>A (p.Arg58His). This variant has been reported in an individuals with aculeiform-cataract (Heon et al 1999. PubMed ID: 10521291). This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.052	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.42	A
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.40
Sift	Benign	0.064	T
Sift4G	Uncertain	0.041	D
Polyphen		0.018	B
Vest4		0.78
MutPred		0.84		Loss of stability (P = 0.0914);
MVP		0.83
MPC		0.35
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.56
gMVP		0.59

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: rs121909596; hg19: chr2-208988912;