rs2071862

Variant names:

• chr22-26625437-G-A
• rs2071862
• NM_001886.3:c.159-44G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-26625437-G-A
• chr22-26625437-G-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.159-44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,607,116 control chromosomes in the GnomAD database, including 20,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2078 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18888 hom.)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0830

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=-0.85).
• BP6: Variant 22-26625437-G-A is Benign according to our data. Variant chr22-26625437-G-A is described in ClinVar as [Benign]. Clinvar id is 677231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	NM_001886.3	c.159-44G>A		intron_variant	Intron 3 of 5	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4	c.174-44G>A		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.159-44G>A		intron_variant	Intron 3 of 5	1	NM_001886.3	ENSP00000346805.3
CRYBA4	ENST00000466315.1	n.56-44G>A		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23509 AN: 152008 Hom.: 2076 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.181 AC: 44975 AN: 248440 Hom.: 4720 AF XY: 0.181 AC XY: 24339 AN XY: 134348

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.391

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.152 AC: 221583 AN: 1454990 Hom.: 18888 Cov.: 29 AF XY: 0.155 AC XY: 112149 AN XY: 723622

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.179

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.393

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.155 AC: 23512 AN: 152126 Hom.: 2078 Cov.: 32 AF XY: 0.157 AC XY: 11649 AN XY: 74370

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.384

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.150

Alfa AF: 0.147 Hom.: 3681

Bravo AF: 0.155

Asia WGS AF: 0.241 AC: 836 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.72

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: rs2071862; hg19: chr22-27021401; COSMIC: COSV61321282;