NM_057093.2:c.506G>C

Variant names:

• chr2-218990340-C-G
• rs77427424
• NM_057093.2:c.506G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_057093.2(CRYBA2):​c.506G>C​(p.Arg169Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYBA2 NM_057093.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• cataract 42

  Inheritance: AD, SD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• early-onset anterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057093.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA2	NM_057093.2	MANE Select	c.506G>C	p.Arg169Pro	missense	Exon 4 of 4	NP_476434.1	P53672
	CRYBA2	NM_057094.2		c.506G>C	p.Arg169Pro	missense	Exon 5 of 5	NP_476435.1	P53672

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYBA2	ENST00000295728.7	TSL:1 MANE Select	c.506G>C	p.Arg169Pro	missense	Exon 4 of 4	ENSP00000295728.2	P53672
	CRYBA2	ENST00000392096.6	TSL:1	c.506G>C	p.Arg169Pro	missense	Exon 5 of 5	ENSP00000375946.2	P53672
	CRYBA2	ENST00000941879.1		c.506G>C	p.Arg169Pro	missense	Exon 5 of 5	ENSP00000611938.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251398 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.12
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.54
Sift	Benign	0.034	D
Sift4G	Benign	0.071	T
Polyphen		0.99	D
Vest4		0.79
MutPred		0.47		Loss of solvent accessibility (P = 0.0364)
MVP		0.81
MPC		1.0
ClinPred		0.98	D
GERP RS		-0.57
Varity_R		0.42
gMVP		0.61
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs77427424; hg19: chr2-219855062;