chr2-218992208-T-C

Position:

• chr2-218992208-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_057093.2(CRYBA2):​c.197A>G​(p.Gln66Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYBA2 NM_057093.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.197A>G	p.Gln66Arg	missense_variant	2/4	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.197A>G	p.Gln66Arg	missense_variant	3/5		NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.197A>G	p.Gln66Arg	missense_variant	2/4	1	NM_057093.2	ENSP00000295728.2
CRYBA2	ENST00000392096.6	c.197A>G	p.Gln66Arg	missense_variant	3/5	1		ENSP00000375946.2
CRYBA2	ENST00000453769.1	c.197A>G	p.Gln66Arg	missense_variant	3/4	3		ENSP00000395120.1
CRYBA2	ENST00000490678.1	n.199A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1461372 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726990

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The c.197A>G (p.Q66R) alteration is located in exon 2 (coding exon 2) of the CRYBA2 gene. This alteration results from a A to G substitution at nucleotide position 197, causing the glutamine (Q) at amino acid position 66 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	.;D;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.20	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.015	D;D;D
Sift4G	Benign	0.14	T;T;.
Polyphen		0.55	P;P;.
Vest4		0.46
MutPred		0.55		Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP		0.86
MPC		0.45
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.61
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219856930;