chr22-26622622-C-T

Position:

chr22-26622622-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_001886.3(CRYBA4):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,453,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CRYBA4
NM_001886.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65

Variant links:

Genes affected

CRYBA4 (HGNC:2396): (crystallin beta A4) 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 acidic group member, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

CRYBA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a chain Beta-crystallin A4 (size 194) in uniprot entity CRBA4_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001886.3

BP4

Computational evidence support a benign effect (MetaRNN=0.020404667).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA4	NM_001886.3 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	2/6	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4 linkuse as main transcript	c.41C>T	p.Ala14Val	missense_variant	4/8		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4 linkuse as main transcript	c.26C>T	p.Ala9Val	missense_variant	2/6	1	NM_001886.3	ENSP00000346805	P1
CRYBA4	ENST00000466315.1 linkuse as main transcript	n.42C>T		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000501

AC:

AN:

139772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00140

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251304

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000236

AC:

AN:

1313584

Hom.:

Cov.:

AF XY:

0.0000214

AC XY:

AN XY:

652892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000342

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000588

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000888

Gnomad4 OTH exome

AF:

0.0000393

GnomAD4 genome

AF:

0.0000501

AC:

AN:

139860

Hom.:

Cov.:

AF XY:

0.0000590

AC XY:

AN XY:

67762

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00140

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000153

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 23

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 1027167). This missense change has been observed in individual(s) with cataracts (PMID: 24968223, 28450710, 31555371). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs530186829, gnomAD 0.1%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the CRYBA4 protein (p.Ala9Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.031

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.80

M_CAP

Benign

0.014

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.92

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.27

REVEL

Benign

0.098

Sift

Benign

0.50

Sift4G

Benign

0.39

Polyphen

0.0090

Vest4

0.30

MutPred

0.45

Loss of sheet (P = 0.0357);

MVP

0.57

MPC

0.29

ClinPred

0.032

GERP RS

3.0

Varity_R

0.13

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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