2-218990919-A-G

Variant names:

• chr2-218990919-A-G
• rs775778432
• NM_057093.2:c.379T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_057093.2(CRYBA2):​c.379T>C​(p.Tyr127His) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CRYBA2 NM_057093.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

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 Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.23951274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA2	NM_057093.2	c.379T>C	p.Tyr127His	missense_variant	Exon 3 of 4	ENST00000295728.7	NP_476434.1
CRYBA2	NM_057094.2	c.379T>C	p.Tyr127His	missense_variant	Exon 4 of 5		NP_476435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYBA2	ENST00000295728.7	c.379T>C	p.Tyr127His	missense_variant	Exon 3 of 4	1	NM_057093.2	ENSP00000295728.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251472 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000961

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000567

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379T>C (p.Y127H) alteration is located in exon 3 (coding exon 3) of the CRYBA2 gene. This alteration results from a T to C substitution at nucleotide position 379, causing the tyrosine (Y) at amino acid position 127 to be replaced by a histidine (H). 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	Pathogenic	0.62
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D;D;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		0.63	P;P;.
Vest4		0.72
MutPred		0.72		Gain of disorder (P = 0.0204);Gain of disorder (P = 0.0204);Gain of disorder (P = 0.0204);
MVP		0.85
MPC		1.0
ClinPred		0.25	T
GERP RS		4.6
Varity_R		0.57
gMVP		0.53

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: rs775778432; hg19: chr2-219855641;