rs5761618

Variant names:

• chr22-26597742-T-G
• rs5761618
• ENST00000668614.2:n.252+659T>G

Variant summary

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

The ENST00000668614.2(ENSG00000286326):​n.252+659T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 151,982 control chromosomes in the GnomAD database, including 16,463 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 0.46 (16463 hom., cov: 32)
• Consequence: ENSG00000286326 ENST00000668614.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.315
• Publications: 6 publications found

Genes affected

ENSG00000286326 (HGNC:):

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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	XM_006724140.4	c.-239+659T>G		intron_variant	Intron 2 of 7		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000286326	ENST00000668614.2	n.252+659T>G		intron_variant	Intron 1 of 2
ENSG00000286326	ENST00000840228.1	n.185+659T>G		intron_variant	Intron 1 of 2
ENSG00000286326	ENST00000840229.1	n.234+659T>G		intron_variant	Intron 2 of 2
ENSG00000286326	ENST00000840230.1	n.234+659T>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69596 AN: 151864 Hom.: 16434 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.458 AC: 69669 AN: 151982 Hom.: 16463 Cov.: 32 AF XY: 0.461 AC XY: 34230 AN XY: 74256

African (AFR) AF: 0.578 AC: 23943 AN: 41440

American (AMR) AF: 0.422 AC: 6452 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1846 AN: 3472

East Asian (EAS) AF: 0.511 AC: 2641 AN: 5172

South Asian (SAS) AF: 0.451 AC: 2170 AN: 4808

European-Finnish (FIN) AF: 0.476 AC: 5021 AN: 10550

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.385 AC: 26168 AN: 67958

Other (OTH) AF: 0.454 AC: 955 AN: 2104

Alfa AF: 0.405 Hom.: 11258

Bravo AF: 0.458

Asia WGS AF: 0.460 AC: 1599 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.1
DANN	Benign	0.44
PhyloP100		0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5761618; hg19: chr22-26993706;