chr2-218990305-C-G

Variant names:

• chr2-218990305-C-G
• rs748194398
• NM_057093.2:c.541G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_057093.2(CRYBA2):​c.541G>C​(p.Gly181Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CRYBA2 NM_057093.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70

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 6 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, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.541G>C	p.Gly181Arg	missense_variant	Exon 4 of 4	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.541G>C	p.Gly181Arg	missense_variant	Exon 5 of 5		NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.541G>C	p.Gly181Arg	missense_variant	Exon 4 of 4	1	NM_057093.2	ENSP00000295728.2
CRYBA2	ENST00000392096.6	c.541G>C	p.Gly181Arg	missense_variant	Exon 5 of 5	1		ENSP00000375946.2
CRYBA2	ENST00000487181.1	n.322G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3
CRYBA2	ENST00000496566.5	n.451G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.47
MutPred		0.77		Gain of solvent accessibility (P = 6e-04);Gain of solvent accessibility (P = 6e-04);
MVP		0.95
MPC		1.0
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.58
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs748194398; hg19: chr2-219855027;