2-208124313-A-G

Variant names:

• chr2-208124313-A-G
• rs2242074
• NM_006891.4:c.51T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006891.4(CRYGD):​c.51T>C​(p.Tyr17Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,608,444 control chromosomes in the GnomAD database, including 255,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28162 hom., cov: 33)
  • Exomes 𝑓: 0.56 (227463 hom.)
• Consequence: CRYGD NM_006891.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.446

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-208124313-A-G is Benign according to our data. Variant chr2-208124313-A-G is described in ClinVar as [Benign]. Clinvar id is 260062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208124313-A-G is described in Lovd as [Benign]. Variant chr2-208124313-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.446 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYGD	NM_006891.4	c.51T>C	p.Tyr17Tyr	synonymous_variant	Exon 2 of 3	ENST00000264376.5	NP_008822.2
LOC100507443	NR_038437.1	n.97+5088A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5	c.51T>C	p.Tyr17Tyr	synonymous_variant	Exon 2 of 3	1	NM_006891.4	ENSP00000264376.4

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91350 AN: 152014 Hom.: 28117 Cov.: 33

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.619

GnomAD3 exomes AF: 0.584 AC: 138623 AN: 237444 Hom.: 40915 AF XY: 0.591 AC XY: 76354 AN XY: 129272

Gnomad AFR exome AF: 0.719

Gnomad AMR exome AF: 0.504

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.664

Gnomad SAS exome AF: 0.733

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.535

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.555 AC: 808610 AN: 1456312 Hom.: 227463 Cov.: 86 AF XY: 0.561 AC XY: 405857 AN XY: 724068

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.505

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 0.652

Gnomad4 SAS exome AF: 0.733

Gnomad4 FIN exome AF: 0.528

Gnomad4 NFE exome AF: 0.530

Gnomad4 OTH exome AF: 0.588

GnomAD4 genome AF: 0.601 AC: 91445 AN: 152132 Hom.: 28162 Cov.: 33 AF XY: 0.604 AC XY: 44932 AN XY: 74366

Gnomad4 AFR AF: 0.724

Gnomad4 AMR AF: 0.546

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.741

Gnomad4 FIN AF: 0.536

Gnomad4 NFE AF: 0.532

Gnomad4 OTH AF: 0.622

Alfa AF: 0.573 Hom.: 11751

Bravo AF: 0.604

Asia WGS AF: 0.708 AC: 2461 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cataract 4 multiple types Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Mar 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aculeiform cataract Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.2
DANN	Benign	0.67

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: rs2242074; hg19: chr2-208989037; COSMIC: COSV99965248; COSMIC: COSV99965248;