2-208142835-T-G

Position:

chr2-208142835-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005210.4(CRYGB):c.331A>C(p.Ile111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.723 in 1,613,576 control chromosomes in the GnomAD database, including 424,582 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37008 hom., cov: 32)

Exomes 𝑓: 0.73 ( 387574 hom. )

Consequence

CRYGB
NM_005210.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

CRYGB (HGNC:2409): (crystallin gamma B) 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]

CRYGB 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=9.3028444E-7).

BP6

Variant 2-208142835-T-G is Benign according to our data. Variant chr2-208142835-T-G is described in ClinVar as [Benign]. Clinvar id is 677166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-208142835-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGB	NM_005210.4 linkuse as main transcript	c.331A>C	p.Ile111Leu	missense_variant	3/3	ENST00000260988.5	NP_005201.2	P07316
CRYGB	XM_017003402.2 linkuse as main transcript	c.337A>C	p.Ile113Leu	missense_variant	3/3		XP_016858891.1
LOC100507443	NR_038437.1 linkuse as main transcript	n.221+5656T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGB	ENST00000260988.5 linkuse as main transcript	c.331A>C	p.Ile111Leu	missense_variant	3/3	1	NM_005210.4	ENSP00000260988.4		P07316

Frequencies

GnomAD3 genomes

AF:

0.695

AC:

105615

AN:

151972

Hom.:

36973

Cov.:

show subpopulations

Gnomad AFR

AF:

0.674

Gnomad AMI

AF:

0.642

Gnomad AMR

AF:

0.593

Gnomad ASJ

AF:

0.720

Gnomad EAS

AF:

0.548

Gnomad SAS

AF:

0.708

Gnomad FIN

AF:

0.711

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.738

Gnomad OTH

AF:

0.686

GnomAD3 exomes

AF:

0.685

AC:

171525

AN:

250534

Hom.:

59576

AF XY:

0.692

AC XY:

93755

AN XY:

135436

show subpopulations

Gnomad AFR exome

AF:

0.663

Gnomad AMR exome

AF:

0.543

Gnomad ASJ exome

AF:

0.727

Gnomad EAS exome

AF:

0.544

Gnomad SAS exome

AF:

0.718

Gnomad FIN exome

AF:

0.709

Gnomad NFE exome

AF:

0.736

Gnomad OTH exome

AF:

0.699

GnomAD4 exome

AF:

0.726

AC:

1061384

AN:

1461486

Hom.:

387574

Cov.:

AF XY:

0.727

AC XY:

528611

AN XY:

727050

show subpopulations

Gnomad4 AFR exome

AF:

0.671

Gnomad4 AMR exome

AF:

0.548

Gnomad4 ASJ exome

AF:

0.733

Gnomad4 EAS exome

AF:

0.527

Gnomad4 SAS exome

AF:

0.718

Gnomad4 FIN exome

AF:

0.711

Gnomad4 NFE exome

AF:

0.744

Gnomad4 OTH exome

AF:

0.717

GnomAD4 genome

AF:

0.695

AC:

105713

AN:

152090

Hom.:

37008

Cov.:

AF XY:

0.692

AC XY:

51468

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.675

Gnomad4 AMR

AF:

0.593

Gnomad4 ASJ

AF:

0.720

Gnomad4 EAS

AF:

0.548

Gnomad4 SAS

AF:

0.708

Gnomad4 FIN

AF:

0.711

Gnomad4 NFE

AF:

0.738

Gnomad4 OTH

AF:

0.688

Alfa

AF:

0.726

Hom.:

86278

Bravo

AF:

0.683

TwinsUK

AF:

0.741

AC:

2749

ALSPAC

AF:

0.734

AC:

2829

ESP6500AA

AF:

0.676

AC:

2978

ESP6500EA

AF:

0.737

AC:

6334

ExAC

AF:

0.688

AC:

83572

Asia WGS

AF:

0.630

AC:

2190

AN:

3478

EpiCase

AF:

0.741

EpiControl

AF:

0.732

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	GeneDx	Mar 24, 2018	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. -

Cataract 39 multiple types

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.10

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.28

MetaRNN

Benign

9.3e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.5

PrimateAI

Benign

0.22

PROVEAN

Benign

0.12

REVEL

Benign

0.13

Sift

Benign

0.080

Sift4G

Uncertain

0.025

Polyphen

0.0

Vest4

0.028

MPC

0.054

ClinPred

0.010

GERP RS

0.47

Varity_R

0.11

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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