chr2-208128226-G-A

Position:

chr2-208128226-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_020989.4(CRYGC):c.502C>T(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000671 in 1,614,202 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R168Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 18 hom. )

Consequence

CRYGC
NM_020989.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0780

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a domain Beta/gamma crystallin 'Greek key' 4 (size 42) in uniprot entity CRGC_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_020989.4

BP4

Computational evidence support a benign effect (MetaRNN=0.023029655).

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYGC	NM_020989.4 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	3/3	ENST00000282141.4
LOC100507443	NR_038437.1 linkuse as main transcript	n.98-8830G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYGC	ENST00000282141.4 linkuse as main transcript	c.502C>T	p.Arg168Trp	missense_variant	3/3	1	NM_020989.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00158

AC:

396

AN:

251426

Hom.:

AF XY:

0.00204

AC XY:

277

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0118

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000707

AC:

1033

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

737

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0110

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000328

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00911

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000662

Hom.:

Bravo

AF:

0.000238

ExAC

AF:

0.00166

AC:

201

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cataract 2, multiple types

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg168Trp variant in CRYGC has been identified in 2 relatives from 1 family with cataracts (PMID: 12011157), but has also been identified in >1% of chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant cataracts. -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 26, 2007	- -

Nuclear pulverulent cataract

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 168 of the CRYGC protein (p.Arg168Trp). This variant is present in population databases (rs28931604, gnomAD 1.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with congenital cataracts (PMID: 17679936, 18587492). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16945). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Benign

0.12

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.27

MetaRNN

Benign

0.023

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0080

Sift4G

Pathogenic

0.0

Polyphen

0.96

Vest4

0.60

MVP

0.90

MPC

0.40

ClinPred

0.24

GERP RS

-0.34

Varity_R

0.52

gMVP

0.72

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