2-208121822-C-T

Position:

chr2-208121822-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_006891.4(CRYGD):c.376G>A(p.Val126Met) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,614,118 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 9 hom. )

Consequence

CRYGD
NM_006891.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.02

Variant links:

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]

CRYGD links:

LOC100507443 (HGNC:):

LOC100507443 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Gamma-crystallin D (size 172) in uniprot entity CRGD_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_006891.4

BP4

Computational evidence support a benign effect (MetaRNN=0.01816386).

BP6

Variant 2-208121822-C-T is Benign according to our data. Variant chr2-208121822-C-T is described in ClinVar as [Benign]. Clinvar id is 333869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208121822-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00211 (321/152228) while in subpopulation NFE AF= 0.00396 (269/68004). AF 95% confidence interval is 0.00357. There are 0 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 321 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGD	NM_006891.4 linkuse as main transcript	c.376G>A	p.Val126Met	missense_variant	3/3	ENST00000264376.5	NP_008822.2	P07320A0A140CTX7
LOC100507443	NR_038437.1 linkuse as main transcript	n.97+2597C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5 linkuse as main transcript	c.376G>A	p.Val126Met	missense_variant	3/3	1	NM_006891.4	ENSP00000264376.4		P07320

Frequencies

GnomAD3 genomes

AF:

0.00211

AC:

321

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00396

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00190

AC:

479

AN:

251480

Hom.:

AF XY:

0.00187

AC XY:

254

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00359

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00247

AC:

3609

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

1788

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00178

Gnomad4 NFE exome

AF:

0.00301

Gnomad4 OTH exome

AF:

0.00147

GnomAD4 genome

AF:

0.00211

AC:

321

AN:

152228

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.00396

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00307

Hom.:

Bravo

AF:

0.00168

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00208

AC:

253

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CRYGD: BS1, BS2 -

Cataract 4 multiple types

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

CRYGD-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Aculeiform cataract

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.87

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.018

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

4.3

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.029

Polyphen

1.0

Vest4

0.26

MVP

0.90

MPC

0.84

ClinPred

0.14

GERP RS

3.4

Varity_R

0.80

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over