chr1-81943716-A-G

Position:

• chr1-81943716-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001366006.2(ADGRL2):​c.1157A>G​(p.Asn386Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADGRL2 NM_001366006.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

Genes affected

ADGRL2 (HGNC:18582): (adhesion G protein-coupled receptor L2) This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors. The encoded protein participates in the regulation of exocytosis. The proprotein is thought to be further cleaved within a cysteine-rich G-protein-coupled receptor proteolysis site into two chains that are non-covalently bound at the cell membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRL2	NM_001366006.2	c.1157A>G	p.Asn386Ser	missense_variant	6/24	ENST00000686636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRL2	ENST00000686636.1	c.1157A>G	p.Asn386Ser	missense_variant	6/24		NM_001366006.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461456 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727012

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 29, 2023

The c.1145A>G (p.N382S) alteration is located in exon 5 (coding exon 4) of the ADGRL2 gene. This alteration results from a A to G substitution at nucleotide position 1145, causing the asparagine (N) at amino acid position 382 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;.;D;.;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D;D;D;D;D;.;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.016	D;D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;.;.;.;D;D;D;D;.;.
Vest4		0.65
MutPred		0.90		.;Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);Loss of sheet (P = 0.1501);
MVP		0.66
MPC		1.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.56
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: rs1648828998; hg19: chr1-82409400;