chr22-26622801-T-C

Position:

• chr22-26622801-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001886.3(CRYBA4):​c.39+166T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 152,222 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.045 (199 hom., cov: 32)
• Consequence: CRYBA4 NM_001886.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.650

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 22-26622801-T-C is Benign according to our data. Variant chr22-26622801-T-C is described in ClinVar as [Benign]. Clinvar id is 1281925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA4	NM_001886.3	c.39+166T>C		intron_variant		ENST00000354760.4	NP_001877.1
CRYBA4	XM_006724140.4	c.54+166T>C		intron_variant			XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA4	ENST00000354760.4	c.39+166T>C		intron_variant		1	NM_001886.3	ENSP00000346805	P1
CRYBA4	ENST00000466315.1	n.55+166T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6806 AN: 152104 Hom.: 199 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.0677

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0478

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

GnomAD4 genome AF: 0.0448 AC: 6819 AN: 152222 Hom.: 199 Cov.: 32 AF XY: 0.0482 AC XY: 3590 AN XY: 74418

Gnomad4 AFR AF: 0.0442

Gnomad4 AMR AF: 0.0364

Gnomad4 ASJ AF: 0.0531

Gnomad4 EAS AF: 0.0936

Gnomad4 SAS AF: 0.0680

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.0411 Hom.: 16

Bravo AF: 0.0382

Asia WGS AF: 0.131 AC: 454 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs79804759; hg19: chr22-27018765; COSMIC: COSV53234816; COSMIC: COSV53234816;