2-218993228-C-G

Position:

• chr2-218993228-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_057093.2(CRYBA2):​c.-52G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,527,876 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (9 hom.)
• Consequence: CRYBA2 NM_057093.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.54

Genes affected

CRYBA2 (HGNC:2395): (crystallin beta A2) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of the vertebrate eye, which function to maintain 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 defined 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 but absent in the acidic group). Beta-crystallins form aggregates of different sizes and are able to form homodimers through self-association or heterodimers with other beta-crystallins. This gene is a beta acidic group member. Three alternatively spliced transcript variants encoding identical proteins have been reported. [provided by RefSeq, Jul 2008]

CRYBA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-218993228-C-G is Benign according to our data. Variant chr2-218993228-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1318253.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00602 (916/152202) while in subpopulation AFR AF= 0.0203 (843/41546). AF 95% confidence interval is 0.0192. There are 10 homozygotes in gnomad4. There are 418 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.-52G>C		5_prime_UTR_variant	1/4	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.-4-48G>C		intron_variant			NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.-52G>C		5_prime_UTR_variant	1/4	1	NM_057093.2	ENSP00000295728.2
CRYBA2	ENST00000392096.6	c.-4-48G>C		intron_variant		1		ENSP00000375946.2
CRYBA2	ENST00000453769.1	c.-52G>C		5_prime_UTR_variant	2/4	3		ENSP00000395120.1
CRYBA2	ENST00000490678.1	n.-50G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 911 AN: 152084 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00147 AC: 198 AN: 134330 Hom.: 2 AF XY: 0.00114 AC XY: 85 AN XY: 74544

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.000130

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000517

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.000778 AC: 1070 AN: 1375674 Hom.: 9 Cov.: 28 AF XY: 0.000723 AC XY: 491 AN XY: 678902

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.0000405

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000630

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00602 AC: 916 AN: 152202 Hom.: 10 Cov.: 32 AF XY: 0.00562 AC XY: 418 AN XY: 74416

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00440 Hom.: 0

Bravo AF: 0.00691

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150356724; hg19: chr2-219857950;