22-26625437-G-A

Variant names:

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

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.159-44G>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
• Publications: 15 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=-0.85).
• BP6: Variant 22-26625437-G-A is Benign according to our data. Variant chr22-26625437-G-A is described in ClinVar as Benign. ClinVar VariationId 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

GnomAD2 exomes AF: 0.181 AC: 44975 AN: 248440 AF XY: 0.181

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 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

African (AFR) AF: 0.136 AC: 4530 AN: 33364

American (AMR) AF: 0.179 AC: 8001 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 5419 AN: 26020

East Asian (EAS) AF: 0.393 AC: 15549 AN: 39584

South Asian (SAS) AF: 0.236 AC: 20290 AN: 86002

European-Finnish (FIN) AF: 0.138 AC: 7094 AN: 51338

Middle Eastern (MID) AF: 0.172 AC: 992 AN: 5756

European-Non Finnish (NFE) AF: 0.135 AC: 150082 AN: 1108158

Other (OTH) AF: 0.160 AC: 9626 AN: 60170

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

African (AFR) AF: 0.131 AC: 5455 AN: 41512

American (AMR) AF: 0.172 AC: 2634 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 680 AN: 3468

East Asian (EAS) AF: 0.384 AC: 1974 AN: 5146

South Asian (SAS) AF: 0.254 AC: 1222 AN: 4810

European-Finnish (FIN) AF: 0.132 AC: 1399 AN: 10612

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9612 AN: 67972

Other (OTH) AF: 0.150 AC: 317 AN: 2116

Alfa AF: 0.149 Hom.: 7727

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

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.72
PhyloP100		-0.083
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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