rs17670506

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_004076.5(CRYBB3):c.314G>A(p.Arg105Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,614,036 control chromosomes in the GnomAD database, including 2,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 192 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2034 hom. )

Consequence

CRYBB3
NM_004076.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

CRYBB3 (HGNC:2400): (crystallin beta B3) 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. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta basic group member, is part of a gene cluster with beta-A4, beta-B1, and beta-B2. Mutations in this gene result in cataract congenital nuclear autosomal recessive type 2. [provided by RefSeq, Feb 2013]

CRYBB3 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 Beta-crystallin B3 (size 210) in uniprot entity CRBB3_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_004076.5

BP4

Computational evidence support a benign effect (MetaRNN=0.004779279).

BP6

Variant 22-25203882-G-A is Benign according to our data. Variant chr22-25203882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25203882-G-A is described in Lovd as [Likely_benign]. Variant chr22-25203882-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB3	NM_004076.5 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 4 of 6	ENST00000215855.7	NP_004067.1	P26998
CRYBB3	XM_047441147.1 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 3 of 5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 4 of 6	1	NM_004076.5	ENSP00000215855.2		P26998
CRYBB3	ENST00000404334.1 link	c.314G>A	p.Arg105Gln	missense_variant	Exon 4 of 5	3		ENSP00000386123.1		B1AHR5

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6802

AN:

152112

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0346

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.0387

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0251

Gnomad FIN

AF:

0.0362

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0516

Gnomad OTH

AF:

0.0556

GnomAD3 exomes

AF:

0.0429

AC:

10794

AN:

251470

Hom.:

282

AF XY:

0.0433

AC XY:

5884

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0338

Gnomad AMR exome

AF:

0.0317

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.00103

Gnomad SAS exome

AF:

0.0276

Gnomad FIN exome

AF:

0.0397

Gnomad NFE exome

AF:

0.0519

Gnomad OTH exome

AF:

0.0533

GnomAD4 exome

AF:

0.0488

AC:

71299

AN:

1461806

Hom.:

2034

Cov.:

AF XY:

0.0485

AC XY:

35253

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0346

Gnomad4 AMR exome

AF:

0.0337

Gnomad4 ASJ exome

AF:

0.123

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.0275

Gnomad4 FIN exome

AF:

0.0371

Gnomad4 NFE exome

AF:

0.0515

Gnomad4 OTH exome

AF:

0.0541

GnomAD4 genome

AF:

0.0447

AC:

6798

AN:

152230

Hom.:

192

Cov.:

AF XY:

0.0442

AC XY:

3291

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0345

Gnomad4 AMR

AF:

0.0387

Gnomad4 ASJ

AF:

0.128

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0247

Gnomad4 FIN

AF:

0.0362

Gnomad4 NFE

AF:

0.0516

Gnomad4 OTH

AF:

0.0550

Alfa

AF:

0.0534

Hom.:

245

Bravo

AF:

0.0453

TwinsUK

AF:

0.0534

AC:

198

ALSPAC

AF:

0.0522

AC:

201

ESP6500AA

AF:

0.0315

AC:

139

ESP6500EA

AF:

0.0541

AC:

465

ExAC

AF:

0.0425

AC:

5163

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0550

EpiControl

AF:

0.0568

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27307692) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital nuclear cataract

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cataract 22 multiple types

Benign:1

Jan 07, 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

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0048

T;T

MetaSVM

Uncertain

-0.027

MutationAssessor

Uncertain

2.9

M;.

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.68

MPC

0.66

ClinPred

0.018

GERP RS

3.5

Varity_R

0.73

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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