rs4276

chr22-26625461-A-Gchr22-26625461-A-T

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -1.11

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 258486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-26625461-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CRYBA4	NM_001886.3	c.159-20A>G		intron_variant		ENST00000354760.4
CRYBA4	XM_006724140.4	c.174-20A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA4	ENST00000354760.4	c.159-20A>G		intron_variant		1	NM_001886.3	P1
CRYBA4	ENST00000466315.1	n.56-20A>G		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.513 AC: 128364 AN: 250370 Hom.: 34348 AF XY: 0.509 AC XY: 68934 AN XY: 135318

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 SAS exome AF: 0.478

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

Gnomad4 AFR exome AF: 0.760

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.651

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.585

Gnomad4 NFE exome AF: 0.481

Gnomad4 OTH exome AF: 0.524

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

Gnomad4 AFR AF: 0.746

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.572

Gnomad4 EAS AF: 0.649

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.584

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.544

Alfa AF: 0.510 Hom.: 10517

Bravo AF: 0.570

Asia WGS AF: 0.550 AC: 1911 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 23 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.045
Dann	Benign	0.47

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

Other links and lift over

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