2-218991975-T-C

Variant names:

• chr2-218991975-T-C
• rs75770608
• NM_057093.2:c.303+127A>G

Variant summary

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

The NM_057093.2(CRYBA2):​c.303+127A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00986 in 758,540 control chromosomes in the GnomAD database, including 379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (274 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (105 hom.)
• Consequence: CRYBA2 NM_057093.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.53

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-218991975-T-C is Benign according to our data. Variant chr2-218991975-T-C is described in ClinVar as [Benign]. Clinvar id is 1258264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.303+127A>G		intron_variant	Intron 2 of 3	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.303+127A>G		intron_variant	Intron 3 of 4		NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.303+127A>G		intron_variant	Intron 2 of 3	1	NM_057093.2	ENSP00000295728.2
CRYBA2	ENST00000392096.6	c.303+127A>G		intron_variant	Intron 3 of 4	1		ENSP00000375946.2
CRYBA2	ENST00000453769.1	c.303+127A>G		intron_variant	Intron 3 of 3	3		ENSP00000395120.1
CRYBA2	ENST00000490678.1	n.432A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4936 AN: 152264 Hom.: 272 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0229

GnomAD4 exome AF: 0.00417 AC: 2525 AN: 606158 Hom.: 105 Cov.: 8 AF XY: 0.00377 AC XY: 1170 AN XY: 310314

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00832

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00573

Gnomad4 SAS exome AF: 0.00286

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.0325 AC: 4956 AN: 152382 Hom.: 274 Cov.: 32 AF XY: 0.0316 AC XY: 2352 AN XY: 74518

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0372 Hom.: 29

Bravo AF: 0.0361

Asia WGS AF: 0.0230 AC: 78 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.1
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75770608; hg19: chr2-219856697;