chr22-26629915-T-C

Variant names:

• chr22-26629915-T-C
• rs5752359
• NM_001886.3:c.444-425T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001886.3(CRYBA4):​c.444-425T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 135,806 control chromosomes in the GnomAD database, including 4,067 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4067 hom., cov: 32)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.543
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	NM_001886.3	c.444-425T>C		intron_variant	Intron 5 of 5	ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4	c.459-425T>C		intron_variant	Intron 7 of 7		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4	c.444-425T>C		intron_variant	Intron 5 of 5	1	NM_001886.3	ENSP00000346805.3
CRYBA4	ENST00000466315.1	n.341-425T>C		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.241 AC: 32644 AN: 135682 Hom.: 4056 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.241 AC: 32681 AN: 135806 Hom.: 4067 Cov.: 32 AF XY: 0.243 AC XY: 15992 AN XY: 65754

African (AFR) AF: 0.351 AC: 13399 AN: 38144

American (AMR) AF: 0.237 AC: 3078 AN: 12970

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 685 AN: 3170

East Asian (EAS) AF: 0.419 AC: 1995 AN: 4760

South Asian (SAS) AF: 0.308 AC: 1242 AN: 4026

European-Finnish (FIN) AF: 0.175 AC: 1456 AN: 8324

Middle Eastern (MID) AF: 0.158 AC: 43 AN: 272

European-Non Finnish (NFE) AF: 0.165 AC: 10179 AN: 61516

Other (OTH) AF: 0.240 AC: 426 AN: 1774

Alfa AF: 0.190 Hom.: 379

Bravo AF: 0.224

Asia WGS AF: 0.254 AC: 882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.93
DANN	Benign	0.21
PhyloP100		-0.54
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: rs5752359; hg19: chr22-27025879;