rs4276

Variant names:

• chr22-26625461-A-G
• rs4276
• NM_001886.3:c.159-20A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-26625461-A-G
• chr22-26625461-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001886.3(CRYBA4):​c.159-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 1,610,650 control chromosomes in the GnomAD database, including 208,852 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26129 hom., cov: 31)
  • Exomes 𝑓: 0.50 (182723 hom.)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.11
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• cataract 23

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 22-26625461-A-G is Benign according to our data. Variant chr22-26625461-A-G is described in ClinVar as Benign. ClinVar VariationId is 258486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	NM_001886.3	c.159-20A>G		intron_variant	Intron 3 of 5	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4	c.174-20A>G		intron_variant	Intron 5 of 7		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4	c.159-20A>G		intron_variant	Intron 3 of 5	1	NM_001886.3	ENSP00000346805.3
CRYBA4	ENST00000466315.1	n.56-20A>G		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87199 AN: 151882 Hom.: 26113 Cov.: 31

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.485

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.513 AC: 128364 AN: 250370 AF XY: 0.509

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.654

Gnomad FIN exome AF: 0.588

Gnomad NFE exome AF: 0.486

Gnomad OTH exome AF: 0.499

GnomAD4 exome AF: 0.496 AC: 723674 AN: 1458650 Hom.: 182723 Cov.: 40 AF XY: 0.496 AC XY: 359598 AN XY: 725682

African (AFR) AF: 0.760 AC: 25422 AN: 33430

American (AMR) AF: 0.386 AC: 17242 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 15000 AN: 26106

East Asian (EAS) AF: 0.651 AC: 25810 AN: 39668

South Asian (SAS) AF: 0.477 AC: 41131 AN: 86154

European-Finnish (FIN) AF: 0.585 AC: 30897 AN: 52786

Middle Eastern (MID) AF: 0.535 AC: 3084 AN: 5764

European-Non Finnish (NFE) AF: 0.481 AC: 533485 AN: 1109768

Other (OTH) AF: 0.524 AC: 31603 AN: 60290

GnomAD4 genome AF: 0.574 AC: 87259 AN: 152000 Hom.: 26129 Cov.: 31 AF XY: 0.576 AC XY: 42766 AN XY: 74290

African (AFR) AF: 0.746 AC: 30948 AN: 41466

American (AMR) AF: 0.478 AC: 7305 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1987 AN: 3472

East Asian (EAS) AF: 0.649 AC: 3338 AN: 5146

South Asian (SAS) AF: 0.487 AC: 2346 AN: 4820

European-Finnish (FIN) AF: 0.584 AC: 6172 AN: 10566

Middle Eastern (MID) AF: 0.479 AC: 139 AN: 290

European-Non Finnish (NFE) AF: 0.491 AC: 33383 AN: 67940

Other (OTH) AF: 0.544 AC: 1150 AN: 2114

Alfa AF: 0.511 Hom.: 11676

Bravo AF: 0.570

Asia WGS AF: 0.550 AC: 1911 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 23 Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.045
DANN	Benign	0.47
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4276; hg19: chr22-27021425; COSMIC: COSV61321450;