22-25202694-G-T

Position:

chr22-25202694-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM2BP4_StrongBP6BS1

The NM_004076.5(CRYBB3):c.96G>T(p.Glu32Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000183 in 1,614,052 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CRYBB3
NM_004076.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.63

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 Likely_benign. Variant got -5 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043239444).

BP6

Variant 22-25202694-G-T is Benign according to our data. Variant chr22-25202694-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1955730.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00107 (163/152340) while in subpopulation AFR AF= 0.00382 (159/41586). AF 95% confidence interval is 0.00334. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB3	NM_004076.5 linkuse as main transcript	c.96G>T	p.Glu32Asp	missense_variant	3/6	ENST00000215855.7	NP_004067.1	P26998
CRYBB3	XM_047441147.1 linkuse as main transcript	c.96G>T	p.Glu32Asp	missense_variant	2/5		XP_047297103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB3	ENST00000215855.7 linkuse as main transcript	c.96G>T	p.Glu32Asp	missense_variant	3/6	1	NM_004076.5	ENSP00000215855.2		P26998
CRYBB3	ENST00000404334.1 linkuse as main transcript	c.96G>T	p.Glu32Asp	missense_variant	3/5	3		ENSP00000386123.1		B1AHR5

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00383

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000306

AC:

AN:

251326

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00413

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

152340

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00382

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000539

Hom.:

Bravo

AF:

0.00117

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000362

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.96G>T (p.E32D) alteration is located in exon 3 (coding exon 2) of the CRYBB3 gene. This alteration results from a G to T substitution at nucleotide position 96, causing the glutamic acid (E) at amino acid position 32 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cataract 22 multiple types

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.043

T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

D;.

Vest4

0.78

MutPred

0.55

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.86

MPC

0.61

ClinPred

0.064

GERP RS

3.4

Varity_R

0.79

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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