rs56117601

Positions:

chr22-26625625-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001886.3(CRYBA4):c.300+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0488 in 1,613,254 control chromosomes in the GnomAD database, including 2,420 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 375 hom., cov: 32)

Exomes 𝑓: 0.047 ( 2045 hom. )

Consequence

CRYBA4
NM_001886.3 splice_region, intron

Scores

Splicing: ADA: 0.01743

Clinical Significance

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

Conservation

PhyloP100: 2.10

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:

CRYBA4 (HGNC:):

CRYBA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 22-26625625-A-G is Benign according to our data. Variant chr22-26625625-A-G is described in ClinVar as [Benign]. Clinvar id is 258488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26625625-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA4	NM_001886.3 linkuse as main transcript	c.300+3A>G		splice_region_variant, intron_variant		ENST00000354760.4	NP_001877.1	P53673A0A097PIJ6
CRYBA4	XM_006724140.4 linkuse as main transcript	c.315+3A>G		splice_region_variant, intron_variant			XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4 linkuse as main transcript	c.300+3A>G		splice_region_variant, intron_variant		1	NM_001886.3	ENSP00000346805.3		P53673
CRYBA4	ENST00000466315.1 linkuse as main transcript	n.197+3A>G		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0643

AC:

9766

AN:

151978

Hom.:

375

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0810

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.0555

Gnomad ASJ

AF:

0.0853

Gnomad EAS

AF:

0.0959

Gnomad SAS

AF:

0.0727

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.0722

GnomAD3 exomes

AF:

0.0605

AC:

15167

AN:

250636

Hom.:

562

AF XY:

0.0606

AC XY:

8206

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.0795

Gnomad AMR exome

AF:

0.0329

Gnomad ASJ exome

AF:

0.0772

Gnomad EAS exome

AF:

0.101

Gnomad SAS exome

AF:

0.0659

Gnomad FIN exome

AF:

0.119

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0627

GnomAD4 exome

AF:

0.0472

AC:

69012

AN:

1461158

Hom.:

2045

Cov.:

AF XY:

0.0478

AC XY:

34771

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.0845

Gnomad4 AMR exome

AF:

0.0362

Gnomad4 ASJ exome

AF:

0.0792

Gnomad4 EAS exome

AF:

0.0800

Gnomad4 SAS exome

AF:

0.0635

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.0391

Gnomad4 OTH exome

AF:

0.0605

GnomAD4 genome

AF:

0.0643

AC:

9779

AN:

152096

Hom.:

375

Cov.:

AF XY:

0.0675

AC XY:

5019

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0810

Gnomad4 AMR

AF:

0.0554

Gnomad4 ASJ

AF:

0.0853

Gnomad4 EAS

AF:

0.0952

Gnomad4 SAS

AF:

0.0729

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.0439

Gnomad4 OTH

AF:

0.0752

Alfa

AF:

0.0508

Hom.:

Bravo

AF:

0.0576

Asia WGS

AF:

0.134

AC:

466

AN:

3478

EpiCase

AF:

0.0473

EpiControl

AF:

0.0476

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	clinical testing	GeneDx	May 01, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.017

dbscSNV1_RF

Benign

0.27

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: -3

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