2-208129550-C-T

Position:

chr2-208129550-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000282141.4(CRYGC):c.143G>A(p.Arg48His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,614,176 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 19 hom., cov: 33)

Exomes 𝑓: 0.017 ( 346 hom. )

Consequence

CRYGC
ENST00000282141.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.12

Variant links:

Genes affected

CRYGC (HGNC:2410): (crystallin gamma C) This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute the major proteins of vertebrate eye lens and maintain the transparency and refractive index of the lens. This gene and several family members are present in a gene cluster on chromosome 2. Mutations in this gene have been shown to cause multiple types of cataract, including Coppock-like cataract and zonular pulverulent cataract, among others. [provided by RefSeq, Jan 2015]

CRYGC links:

LOC100507443 (HGNC:):

LOC100507443 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005558312).

BP6

Variant 2-208129550-C-T is Benign according to our data. Variant chr2-208129550-C-T is described in ClinVar as [Benign]. Clinvar id is 402565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0117 (1776/152284) while in subpopulation SAS AF= 0.0483 (233/4822). AF 95% confidence interval is 0.0432. There are 19 homozygotes in gnomad4. There are 861 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1776 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGC	NM_020989.4 linkuse as main transcript	c.143G>A	p.Arg48His	missense_variant	2/3	ENST00000282141.4	NP_066269.1
LOC100507443	NR_038437.1 linkuse as main transcript	n.98-7506C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGC	ENST00000282141.4 linkuse as main transcript	c.143G>A	p.Arg48His	missense_variant	2/3	1	NM_020989.4	ENSP00000282141	P1

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1775

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0481

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0138

GnomAD3 exomes

AF:

0.0168

AC:

4221

AN:

251486

Hom.:

AF XY:

0.0189

AC XY:

2565

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0531

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0175

AC:

25556

AN:

1461892

Hom.:

346

Cov.:

AF XY:

0.0184

AC XY:

13370

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.00669

Gnomad4 ASJ exome

AF:

0.00348

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0511

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.0168

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0117

AC:

1776

AN:

152284

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

861

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00291

Gnomad4 AMR

AF:

0.00693

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0483

Gnomad4 FIN

AF:

0.0161

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0144

Hom.:

Bravo

AF:

0.00961

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0174

AC:

2112

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0149

EpiControl

AF:

0.0148

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	clinical testing	GeneDx	Sep 22, 2018	This variant is associated with the following publications: (PMID: 23954869, 21423869, 27884173, 27535533, 29386872) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 4/4 individuals (1 family ) affected with AD pulvurent congenital cataract and was absent from 10 healthy relatives and 230 ethnically matched healthy controls (Gonzalez-Huerta_2013). It has also been reported in 4/30 cases og congenital cataract (Kumar_2011). The exact prevalence of congenital cataract is unknown but estimated around 1-6/10,000 children. The frequency of the variant in South Asians in 5.3%. -

Usher syndrome type 2C

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Arg48His variant in CRYGC has been identified in 4 individuals with cataracts in the literature (PMID: 21423869). However, this variant is classified as benign for autosomal dominant cataracts because it has been identified in >5% of South Asian chromosomes by ExAC (http://gnomad.broadinstitute.org/). -

Nuclear pulverulent cataract

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.12

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.88

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Benign

0.26

Sift4G

Benign

0.70

Polyphen

0.12

Vest4

0.083

MPC

0.13

ClinPred

0.012

GERP RS

1.1

Varity_R

0.11

gMVP

0.39

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