22-26623190-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001886.3(CRYBA4):c.40-44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,527,618 control chromosomes in the GnomAD database, including 1,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (202 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1222 hom.)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.49

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 22-26623190-G-A is Benign according to our data. Variant chr22-26623190-G-A is described in ClinVar as [Benign]. Clinvar id is 1221696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYBA4	NM_001886.3	c.40-44G>A		intron_variant		ENST00000354760.4
CRYBA4	XM_006724140.4	c.55-44G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYBA4	ENST00000354760.4	c.40-44G>A		intron_variant		1	NM_001886.3	P1
CRYBA4	ENST00000466315.1	n.55+555G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6830 AN: 152142 Hom.: 202 Cov.: 32

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.0680

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0326

Gnomad OTH AF: 0.0475

GnomAD3 exomes AF: 0.0476 AC: 11654 AN: 244618 Hom.: 365 AF XY: 0.0481 AC XY: 6400 AN XY: 133144

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0445

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0617

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0341

Gnomad OTH exome AF: 0.0460

GnomAD4 exome AF: 0.0356 AC: 48947 AN: 1375360 Hom.: 1222 Cov.: 22 AF XY: 0.0365 AC XY: 25165 AN XY: 689094

Gnomad4 AFR exome AF: 0.0473

Gnomad4 AMR exome AF: 0.0252

Gnomad4 ASJ exome AF: 0.0464

Gnomad4 EAS exome AF: 0.0792

Gnomad4 SAS exome AF: 0.0584

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0282

Gnomad4 OTH exome AF: 0.0448

GnomAD4 genome AF: 0.0449 AC: 6843 AN: 152258 Hom.: 202 Cov.: 32 AF XY: 0.0485 AC XY: 3607 AN XY: 74438

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.0365

Gnomad4 ASJ AF: 0.0530

Gnomad4 EAS AF: 0.0947

Gnomad4 SAS AF: 0.0683

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0326

Gnomad4 OTH AF: 0.0508

Alfa AF: 0.0279 Hom.: 25

Bravo AF: 0.0383

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.19
Dann	Benign	0.66

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

Other links and lift over

dbSNP: rs74847916; hg19: chr22-27019154; COSMIC: COSV61323029;