chr22-25227872-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000496.3(CRYBB2):c.193G>T(p.Ala65Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,088 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 24 hom., cov: 28)

Exomes 𝑓: 0.013 ( 261 hom. )

Consequence

CRYBB2
NM_000496.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.80

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:

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 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=0.0042724013).

BP6

Variant 22-25227872-G-T is Benign according to our data. Variant chr22-25227872-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-25227872-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0161 (2446/152218) while in subpopulation SAS AF= 0.044 (212/4820). AF 95% confidence interval is 0.0391. There are 24 homozygotes in gnomad4. There are 1210 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2446 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBB2	NM_000496.3 link	c.193G>T	p.Ala65Ser	missense_variant	Exon 4 of 6	ENST00000398215.3	NP_000487.1	P43320R4UMM2
CRYBB2	XM_006724141.4 link	c.193G>T	p.Ala65Ser	missense_variant	Exon 4 of 6		XP_006724204.1	P43320R4UMM2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBB2	ENST00000398215.3 link	c.193G>T	p.Ala65Ser	missense_variant	Exon 4 of 6	1	NM_000496.3	ENSP00000381273.2		P43320
CRYBB2	ENST00000651629.1 link	c.193G>T	p.Ala65Ser	missense_variant	Exon 4 of 6			ENSP00000498905.1		P43320

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2436

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0255

Gnomad AMI

AF:

0.0242

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.0435

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0163

AC:

4108

AN:

251372

Hom.:

AF XY:

0.0177

AC XY:

2400

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0277

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.00466

Gnomad EAS exome

AF:

0.0135

Gnomad SAS exome

AF:

0.0474

Gnomad FIN exome

AF:

0.0212

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0131

AC:

19158

AN:

1461870

Hom.:

261

Cov.:

AF XY:

0.0143

AC XY:

10399

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0231

Gnomad4 AMR exome

AF:

0.00347

Gnomad4 ASJ exome

AF:

0.00570

Gnomad4 EAS exome

AF:

0.00741

Gnomad4 SAS exome

AF:

0.0467

Gnomad4 FIN exome

AF:

0.0211

Gnomad4 NFE exome

AF:

0.0106

Gnomad4 OTH exome

AF:

0.0144

GnomAD4 genome

AF:

0.0161

AC:

2446

AN:

152218

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1210

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0255

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.0103

Gnomad4 SAS

AF:

0.0440

Gnomad4 FIN

AF:

0.0214

Gnomad4 NFE

AF:

0.0109

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0123

Hom.:

Bravo

AF:

0.0147

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.0309

AC:

136

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.0173

AC:

2105

Asia WGS

AF:

0.0560

AC:

195

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Cataract 3 multiple types

Benign:1

Jan 17, 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

0.083

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.11

Eigen

Benign

-0.18

Eigen_PC

Benign

0.0037

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.41

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.14

REVEL

Benign

0.13

Sift

Benign

0.76

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.13

MPC

0.42

ClinPred

0.0030

GERP RS

4.1

Varity_R

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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