Variant 8-37797291-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032777.10(ADGRA2):c.23T>C(p.Met8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,307,652 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ADGRA2
NM_032777.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.267

Variant links:

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]

ADGRA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16253069).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA2	NM_032777.10 linkuse as main transcript	c.23T>C	p.Met8Thr	missense_variant	1/19	ENST00000412232.3	NP_116166.9	Q96PE1-1Q6YN44
ADGRA2	XM_011544481.3 linkuse as main transcript	c.23T>C	p.Met8Thr	missense_variant	1/19		XP_011542783.1
ADGRA2	XM_011544482.3 linkuse as main transcript	c.23T>C	p.Met8Thr	missense_variant	1/18		XP_011542784.1
ADGRA2	XM_011544483.3 linkuse as main transcript	c.23T>C	p.Met8Thr	missense_variant	1/18		XP_011542785.1	D3DSW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRA2	ENST00000412232.3 linkuse as main transcript	c.23T>C	p.Met8Thr	missense_variant	1/19	1	NM_032777.10	ENSP00000406367.2	Q96PE1-1
ADGRA2	ENST00000315215.11 linkuse as main transcript	c.23T>C	p.Met8Thr	missense_variant	1/16	1		ENSP00000323508.7	Q96PE1-2
ADGRA2	ENST00000428068.5 linkuse as main transcript	c.140+12961T>C		intron_variant		3		ENSP00000400860.1	H7C1L1

Frequencies

GnomAD3 genomes

AF:

0.0000923

AC:

AN:

151702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

122

AN:

1155950

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

558368

show subpopulations

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:

0.000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000923

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.0000944

AC XY:

AN XY:

74118

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2024

The c.23T>C (p.M8T) alteration is located in exon 1 (coding exon 1) of the ADGRA2 gene. This alteration results from a T to C substitution at nucleotide position 23, causing the methionine (M) at amino acid position 8 to be replaced by a threonine (T). 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

0.73

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.18

.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.58

T;T

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.067

Sift

Benign

1.0

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0030

B;B

Vest4

0.35

MutPred

0.30

Gain of phosphorylation at M8 (P = 0.0111);Gain of phosphorylation at M8 (P = 0.0111);

MVP

0.38

MPC

0.31

ClinPred

0.048

GERP RS

3.3

Varity_R

0.23

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over