NM_057093.2:c.287G>T

Variant names:

• chr2-218992118-C-A
• rs772123899
• NM_057093.2:c.287G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_057093.2(CRYBA2):​c.287G>T​(p.Arg96Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYBA2 NM_057093.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.02

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain Beta-crystallin A2 (size 196) in uniprot entity CRBA2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_057093.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.287G>T	p.Arg96Leu	missense_variant	Exon 2 of 4	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.287G>T	p.Arg96Leu	missense_variant	Exon 3 of 5		NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.287G>T	p.Arg96Leu	missense_variant	Exon 2 of 4	1	NM_057093.2	ENSP00000295728.2
CRYBA2	ENST00000392096.6	c.287G>T	p.Arg96Leu	missense_variant	Exon 3 of 5	1		ENSP00000375946.2
CRYBA2	ENST00000453769.1	c.287G>T	p.Arg96Leu	missense_variant	Exon 3 of 4	3		ENSP00000395120.1
CRYBA2	ENST00000490678.1	n.289G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.2	M;M;.
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.84
MutPred		0.91		Loss of catalytic residue at R96 (P = 0.0759);Loss of catalytic residue at R96 (P = 0.0759);Loss of catalytic residue at R96 (P = 0.0759);
MVP		0.96
MPC		0.94
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.82
gMVP		0.82

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: rs772123899; hg19: chr2-219856840;