chr22-25221469-T-A

Position:

chr22-25221469-T-A

Variant summary

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

The NM_000496.3(CRYBB2):c.40T>A(p.Ser14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,458 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 108 hom. )

Consequence

CRYBB2
NM_000496.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.75

Variant links:

Genes affected

CRYBB2 (HGNC:2398): (crystallin beta B2) 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-B3. A chain-terminating mutation was found to cause type 2 cerulean cataracts. [provided by RefSeq, Jul 2008]

CRYBB2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Beta-crystallin B2 (size 203) in uniprot entity CRBB2_HUMAN there are 23 pathogenic changes around while only 1 benign (96%) in NM_000496.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0017588735).

BP6

Variant 22-25221469-T-A is Benign according to our data. Variant chr22-25221469-T-A is described in ClinVar as [Benign]. Clinvar id is 667923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBB2	NM_000496.3 linkuse as main transcript	c.40T>A	p.Ser14Thr	missense_variant	2/6	ENST00000398215.3	NP_000487.1
CRYBB2	XM_006724141.4 linkuse as main transcript	c.40T>A	p.Ser14Thr	missense_variant	2/6		XP_006724204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3 linkuse as main transcript	c.40T>A	p.Ser14Thr	missense_variant	2/6	1	NM_000496.3	ENSP00000381273	P1
CRYBB2	ENST00000651629.1 linkuse as main transcript	c.40T>A	p.Ser14Thr	missense_variant	2/6			ENSP00000498905	P1

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

450

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0732

Gnomad SAS

AF:

0.00229

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00581

AC:

1459

AN:

251280

Hom.:

AF XY:

0.00564

AC XY:

766

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0762

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00212

AC:

3101

AN:

1461202

Hom.:

108

Cov.:

AF XY:

0.00214

AC XY:

1558

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0692

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00296

AC:

451

AN:

152256

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0730

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00255

Hom.:

Bravo

AF:

0.00280

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00532

AC:

646

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cataract 3 multiple types

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.070

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.42

MutationTaster

Benign

1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.59

REVEL

Benign

0.068

Sift

Benign

0.46

Sift4G

Benign

0.74

Polyphen

0.0010

Vest4

0.092

MVP

0.43

MPC

0.42

ClinPred

0.0039

GERP RS

1.6

Varity_R

0.050

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