chr22-25225024-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000496.3(CRYBB2):ā€‹c.161T>Gā€‹(p.Val54Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CRYBB2
NM_000496.3 missense

Scores

13
4
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.40
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.977
PP5
Variant 22-25225024-T-G is Pathogenic according to our data. Variant chr22-25225024-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 463969.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CRYBB2NM_000496.3 linkuse as main transcriptc.161T>G p.Val54Gly missense_variant 3/6 ENST00000398215.3 NP_000487.1
CRYBB2XM_006724141.4 linkuse as main transcriptc.161T>G p.Val54Gly missense_variant 3/6 XP_006724204.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CRYBB2ENST00000398215.3 linkuse as main transcriptc.161T>G p.Val54Gly missense_variant 3/61 NM_000496.3 ENSP00000381273 P1
CRYBB2ENST00000651629.1 linkuse as main transcriptc.161T>G p.Val54Gly missense_variant 3/6 ENSP00000498905 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.91e-7
AC:
1
AN:
1446544
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
720808
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.11e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cataract 3 multiple types Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 15, 2017In summary, this variant is a novel missense change that has been shown to be de novo in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CRYBB2-related disease. This sequence change replaces valine with glycine at codon 54 of the CRYBB2 protein (p.Val54Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. Family studies have indicated that this variant was not present in the parents of an individual with congenital cataracts, which suggests that it was de novo in that affected individual (Invitae). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.83
T
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
4.1
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.016
D
Polyphen
1.0
D
Vest4
0.69
MutPred
0.90
Loss of stability (P = 0.0066);
MVP
0.98
MPC
1.5
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs1555888762; hg19: chr22-25620991; API