rs2071861

Variant names:

• chr22-26625225-A-G
• rs2071861
• NM_001886.3:c.159-256A>G

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.159-256A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,036 control chromosomes in the GnomAD database, including 6,515 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.27 (6515 hom., cov: 32)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.53
• Publications: 7 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=-0.9).
• BP6: Variant 22-26625225-A-G is Benign according to our data. Variant chr22-26625225-A-G is described in ClinVar as Benign. ClinVar VariationId is 667637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	NM_001886.3	c.159-256A>G		intron_variant	Intron 3 of 5	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4	c.174-256A>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.159-256A>G		intron_variant	Intron 3 of 5	1	NM_001886.3	ENSP00000346805.3
CRYBA4	ENST00000466315.1	n.56-256A>G		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41664 AN: 151918 Hom.: 6506 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.274 AC: 41710 AN: 152036 Hom.: 6515 Cov.: 32 AF XY: 0.278 AC XY: 20626 AN XY: 74320

African (AFR) AF: 0.403 AC: 16702 AN: 41446

American (AMR) AF: 0.249 AC: 3812 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 980 AN: 3466

East Asian (EAS) AF: 0.489 AC: 2514 AN: 5146

South Asian (SAS) AF: 0.328 AC: 1581 AN: 4814

European-Finnish (FIN) AF: 0.249 AC: 2634 AN: 10594

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12659 AN: 67964

Other (OTH) AF: 0.268 AC: 566 AN: 2112

Alfa AF: 0.240 Hom.: 595

Bravo AF: 0.277

Asia WGS AF: 0.387 AC: 1346 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	-0.90
CADD	Benign	0.15
DANN	Benign	0.55
PhyloP100		-2.5
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: rs2071861; hg19: chr22-27021189; COSMIC: COSV107422487;