22-26599551-C-T

Position:

chr22-26599551-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001887.4(CRYBB1):c.698G>A(p.Arg233His) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CRYBB1
NM_001887.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.76

Variant links:

Genes affected

CRYBB1 (HGNC:2397): (crystallin beta B1) 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, undergoes extensive cleavage at its N-terminal extension during lens maturation. It is also a member of a gene cluster with beta-A4, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

CRYBB1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-26599551-C-T is Pathogenic according to our data. Variant chr22-26599551-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2737022.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CRYBB1	NM_001887.4 linkuse as main transcript	c.698G>A	p.Arg233His	missense_variant	6/6	ENST00000647684.1	NP_001878.1
CRYBB1	XM_011529899.4 linkuse as main transcript	c.698G>A	p.Arg233His	missense_variant	6/6		XP_011528201.1
CRYBA4	XM_006724140.4 linkuse as main transcript	c.-239+2468C>T		intron_variant			XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBB1	ENST00000647684.1 linkuse as main transcript	c.698G>A	p.Arg233His	missense_variant	6/6		NM_001887.4	ENSP00000497249	P1
	ENST00000668614.1 linkuse as main transcript	n.56+2468C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251188

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 17 multiple types

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects CRYBB1 function (PMID: 25086334). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This missense change has been observed in individual(s) with congenital cataract (PMID: 21402992). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs575368335, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 233 of the CRYBB1 protein (p.Arg233His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

.;D

REVEL

Uncertain

0.54

Sift

Benign

0.030

.;D

Sift4G

Uncertain

0.0050

.;D

Polyphen

0.56

P;P

Vest4

0.46

MutPred

0.51

Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);

MVP

0.86

MPC

0.42

ClinPred

0.62

GERP RS

4.2

Varity_R

0.70

gMVP

0.48

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