chr22-26623300-G-A

Position:

chr22-26623300-G-A

Variant summary

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

The NM_001886.3(CRYBA4):c.106G>A(p.Val36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,614,012 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 32)

Exomes 𝑓: 0.021 ( 384 hom. )

Consequence

CRYBA4
NM_001886.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.39

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 Benign. Variant got -18 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=0.0030172765).

BP6

Variant 22-26623300-G-A is Benign according to our data. Variant chr22-26623300-G-A is described in ClinVar as [Benign]. Clinvar id is 258485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26623300-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2532/152278) while in subpopulation NFE AF= 0.025 (1703/68032). AF 95% confidence interval is 0.024. There are 27 homozygotes in gnomad4. There are 1220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2532 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA4	NM_001886.3 linkuse as main transcript	c.106G>A	p.Val36Met	missense_variant	3/6	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4 linkuse as main transcript	c.121G>A	p.Val41Met	missense_variant	5/8		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4 linkuse as main transcript	c.106G>A	p.Val36Met	missense_variant	3/6	1	NM_001886.3	ENSP00000346805	P1
CRYBA4	ENST00000466315.1 linkuse as main transcript	n.55+665G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2531

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.00659

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0433

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.0174

AC:

4372

AN:

251340

Hom.:

AF XY:

0.0180

AC XY:

2441

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.00728

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00359

Gnomad FIN exome

AF:

0.0437

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0212

AC:

30922

AN:

1461734

Hom.:

384

Cov.:

AF XY:

0.0208

AC XY:

15138

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00320

Gnomad4 AMR exome

AF:

0.00745

Gnomad4 ASJ exome

AF:

0.00578

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00436

Gnomad4 FIN exome

AF:

0.0409

Gnomad4 NFE exome

AF:

0.0241

Gnomad4 OTH exome

AF:

0.0151

GnomAD4 genome

AF:

0.0166

AC:

2532

AN:

152278

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1220

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00470

Gnomad4 AMR

AF:

0.00699

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0433

Gnomad4 NFE

AF:

0.0250

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0210

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0248

AC:

213

ExAC

AF:

0.0173

AC:

2100

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0248

EpiControl

AF:

0.0274

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Cataract 23

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.0

REVEL

Benign

0.22

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.16

MPC

0.88

ClinPred

0.015

GERP RS

3.4

Varity_R

0.40

gMVP

0.57

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