2-218993228-C-G

Variant names:

• chr2-218993228-C-G
• rs150356724
• NM_057093.2:c.-52G>C

Variant summary

Our verdict is Benign. The variant received -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]

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.-52G>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.-4-48G>C		intron_variant	Intron 1 of 4		NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.-52G>C		5_prime_UTR_variant	Exon 1 of 4	1	NM_057093.2	ENSP00000295728.2
CRYBA2	ENST00000392096.6	c.-4-48G>C		intron_variant	Intron 1 of 4	1		ENSP00000375946.2
CRYBA2	ENST00000453769.1	c.-52G>C		5_prime_UTR_variant	Exon 2 of 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

GnomAD2 exomes AF: 0.00147 AC: 198 AN: 134330 AF XY: 0.00114

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 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 AC: 614 AN: 30472

Gnomad4 AMR exome AF: 0.00210 AC: 69 AN: 32798

Gnomad4 ASJ exome AF: 0.0000405 AC: 1 AN: 24680

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35316

Gnomad4 SAS exome AF: 0.0000630 AC: 5 AN: 79388

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 43064

Gnomad4 NFE exome AF: 0.000265 AC: 283 AN: 1068650

Gnomad4 Remaining exome AF: 0.00156 AC: 89 AN: 56982

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 AC: 0.0202908 AN: 0.0202908

Gnomad4 AMR AF: 0.00235 AC: 0.00235325 AN: 0.00235325

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207125 AN: 0.000207125

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000456 AC: 0.000456137 AN: 0.000456137

Gnomad4 OTH AF: 0.00236 AC: 0.00236295 AN: 0.00236295

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

Dec 24, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.65
Mutation Taster		=300/0	polymorphism

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;