chr8-37797354-C-T

Position:

• chr8-37797354-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032777.10(ADGRA2):​c.86C>T​(p.Pro29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 1,257,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000072 (0 hom.)
• Consequence: ADGRA2 NM_032777.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.466

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14647278).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA2	NM_032777.10	c.86C>T	p.Pro29Leu	missense_variant	1/19	ENST00000412232.3	NP_116166.9
ADGRA2	XM_011544481.3	c.86C>T	p.Pro29Leu	missense_variant	1/19		XP_011542783.1
ADGRA2	XM_011544482.3	c.86C>T	p.Pro29Leu	missense_variant	1/18		XP_011542784.1
ADGRA2	XM_011544483.3	c.86C>T	p.Pro29Leu	missense_variant	1/18		XP_011542785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA2	ENST00000412232.3	c.86C>T	p.Pro29Leu	missense_variant	1/19	1	NM_032777.10	ENSP00000406367.2
ADGRA2	ENST00000315215.11	c.86C>T	p.Pro29Leu	missense_variant	1/16	1		ENSP00000323508.7
ADGRA2	ENST00000428068.5	c.140+13024C>T		intron_variant		3		ENSP00000400860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000716 AC: 9 AN: 1257740 Hom.: 0 Cov.: 32 AF XY: 0.00000486 AC XY: 3 AN XY: 617718

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: 0.00000787

Gnomad4 OTH exome AF: 0.0000194

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 16, 2024

The c.86C>T (p.P29L) alteration is located in exon 1 (coding exon 1) of the ADGRA2 gene. This alteration results from a C to T substitution at nucleotide position 86, causing the proline (P) at amino acid position 29 to be replaced by a leucine (L). 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	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.020
Sift	Benign	0.47	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0010	B;B
Vest4		0.13
MutPred		0.36		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);
MVP		0.26
MPC		0.28
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.061
gMVP		0.24

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: rs1804359300; hg19: chr8-37654872;