rs75205052

Variant names:

• chr22-26630322-G-A
• rs75205052
• NM_001886.3:c.444-18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000354760.4(CRYBA4):​c.444-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,613,822 control chromosomes in the GnomAD database, including 1,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (151 hom., cov: 34)
  • Exomes 𝑓: 0.034 (1197 hom.)
• Consequence: CRYBA4 ENST00000354760.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.419
• Publications: 5 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=-0.81).
• BP6: Variant 22-26630322-G-A is Benign according to our data. Variant chr22-26630322-G-A is described in ClinVar as Benign. ClinVar VariationId is 258489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0869 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000354760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	NM_001886.3	MANE Select	c.444-18G>A		intron	N/A	NP_001877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA4	ENST00000354760.4	TSL:1 MANE Select	c.444-18G>A		intron	N/A	ENSP00000346805.3
	CRYBA4	ENST00000466315.1	TSL:5	n.341-18G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5148 AN: 152238 Hom.: 153 Cov.: 34

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0450 AC: 11226 AN: 249560 AF XY: 0.0462

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0447

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0340 AC: 49699 AN: 1461466 Hom.: 1197 Cov.: 31 AF XY: 0.0350 AC XY: 25451 AN XY: 727018

African (AFR) AF: 0.00439 AC: 147 AN: 33472

American (AMR) AF: 0.0233 AC: 1044 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1213 AN: 26134

East Asian (EAS) AF: 0.0799 AC: 3170 AN: 39694

South Asian (SAS) AF: 0.0561 AC: 4836 AN: 86200

European-Finnish (FIN) AF: 0.102 AC: 5432 AN: 53338

Middle Eastern (MID) AF: 0.0479 AC: 276 AN: 5760

European-Non Finnish (NFE) AF: 0.0280 AC: 31102 AN: 1111786

Other (OTH) AF: 0.0411 AC: 2479 AN: 60368

GnomAD4 genome AF: 0.0338 AC: 5150 AN: 152356 Hom.: 151 Cov.: 34 AF XY: 0.0378 AC XY: 2818 AN XY: 74496

African (AFR) AF: 0.00568 AC: 236 AN: 41582

American (AMR) AF: 0.0334 AC: 511 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3472

East Asian (EAS) AF: 0.0938 AC: 486 AN: 5184

South Asian (SAS) AF: 0.0661 AC: 319 AN: 4828

European-Finnish (FIN) AF: 0.103 AC: 1097 AN: 10618

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2200 AN: 68038

Other (OTH) AF: 0.0454 AC: 96 AN: 2116

Alfa AF: 0.0348 Hom.: 38

Bravo AF: 0.0258

Asia WGS AF: 0.118 AC: 410 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cataract 23 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.56
PhyloP100		0.42
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: rs75205052; hg19: chr22-27026286; COSMIC: COSV107422490;