8-37797356-G-A

Position:

• chr8-37797356-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032777.10(ADGRA2):​c.88G>A​(p.Glu30Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000318 in 1,257,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: ADGRA2 NM_032777.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.674

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11713761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA2	NM_032777.10	c.88G>A	p.Glu30Lys	missense_variant	1/19	ENST00000412232.3	NP_116166.9
ADGRA2	XM_011544481.3	c.88G>A	p.Glu30Lys	missense_variant	1/19		XP_011542783.1
ADGRA2	XM_011544482.3	c.88G>A	p.Glu30Lys	missense_variant	1/18		XP_011542784.1
ADGRA2	XM_011544483.3	c.88G>A	p.Glu30Lys	missense_variant	1/18		XP_011542785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA2	ENST00000412232.3	c.88G>A	p.Glu30Lys	missense_variant	1/19	1	NM_032777.10	ENSP00000406367.2
ADGRA2	ENST00000315215.11	c.88G>A	p.Glu30Lys	missense_variant	1/16	1		ENSP00000323508.7
ADGRA2	ENST00000428068.5	c.140+13026G>A		intron_variant		3		ENSP00000400860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000318 AC: 4 AN: 1257140 Hom.: 0 Cov.: 32 AF XY: 0.00000486 AC XY: 3 AN XY: 617358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000567

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000589

Gnomad4 NFE exome AF: 9.84e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Dec 15, 2022

The c.88G>A (p.E30K) alteration is located in exon 1 (coding exon 1) of the ADGRA2 gene. This alteration results from a G to A substitution at nucleotide position 88, causing the glutamic acid (E) at amino acid position 30 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	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.049
Sift	Benign	0.36	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.013	B;B
Vest4		0.093
MutPred		0.36		Gain of ubiquitination at E30 (P = 0.0128);Gain of ubiquitination at E30 (P = 0.0128);
MVP		0.23
MPC		0.31
ClinPred		0.084	T
GERP RS		3.6
Varity_R		0.065
gMVP		0.36

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: rs1804359522; hg19: chr8-37654874;