8-37828946-G-A

Position:

• chr8-37828946-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_032777.10(ADGRA2):​c.397G>A​(p.Glu133Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,424,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000035 (1 hom.)
• Consequence: ADGRA2 NM_032777.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.48

Genes affected

ADGRA2 (HGNC:17849): (adhesion G protein-coupled receptor A2) Predicted to enable G protein-coupled receptor activity. Involved in positive regulation of canonical Wnt signaling pathway. Part of Wnt signalosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32612562).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA2	NM_032777.10	c.397G>A	p.Glu133Lys	missense_variant	3/19	ENST00000412232.3	NP_116166.9
ADGRA2	XM_011544481.3	c.397G>A	p.Glu133Lys	missense_variant	3/19		XP_011542783.1
ADGRA2	XM_011544482.3	c.325G>A	p.Glu109Lys	missense_variant	2/18		XP_011542784.1
ADGRA2	XM_011544483.3	c.397G>A	p.Glu133Lys	missense_variant	3/18		XP_011542785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA2	ENST00000412232.3	c.397G>A	p.Glu133Lys	missense_variant	3/19	1	NM_032777.10	ENSP00000406367.2
ADGRA2	ENST00000315215.11	c.397G>A	p.Glu133Lys	missense_variant	3/16	1		ENSP00000323508.7
ADGRA2	ENST00000428068.5	c.271G>A	p.Glu91Lys	missense_variant	3/6	3		ENSP00000400860.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1424772 Hom.: 1 Cov.: 31 AF XY: 0.00000425 AC XY: 3 AN XY: 706164

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ExAC AF: 0.0000165 AC: 2

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

Nov 22, 2024

The c.397G>A (p.E133K) alteration is located in exon 3 (coding exon 3) of the ADGRA2 gene. This alteration results from a G to A substitution at nucleotide position 397, causing the glutamic acid (E) at amino acid position 133 to be replaced by a lysine (K). 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	Benign	0.21
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.62	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.22, 0.31	.;B;B
Vest4		0.54, 0.68
MutPred		0.37		.;Loss of ubiquitination at K135 (P = 0.0318);Loss of ubiquitination at K135 (P = 0.0318);
MVP		0.38
MPC		0.59
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.12
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: rs751263844; hg19: chr8-37686464; COSMIC: COSV59442734;