chr1-81907029-C-T

Position:

• chr1-81907029-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001366006.2(ADGRL2):​c.86C>T​(p.Ala29Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ADGRL2 NM_001366006.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41617686).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL2	NM_001366006.2	c.86C>T	p.Ala29Val	missense_variant	3/24	ENST00000686636.1	NP_001352935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL2	ENST00000686636.1	c.86C>T	p.Ala29Val	missense_variant	3/24		NM_001366006.2	ENSP00000509478.1
ADGRL2	ENST00000370725.5	c.86C>T	p.Ala29Val	missense_variant	6/26	5		ENSP00000359760.1
ADGRL2	ENST00000370723.5	c.86C>T	p.Ala29Val	missense_variant	6/25	5		ENSP00000359758.1
ADGRL2	ENST00000370728.5	c.86C>T	p.Ala29Val	missense_variant	6/25	5		ENSP00000359763.1
ADGRL2	ENST00000370727.5	c.86C>T	p.Ala29Val	missense_variant	6/25	5		ENSP00000359762.1
ADGRL2	ENST00000370730.5	c.86C>T	p.Ala29Val	missense_variant	6/24	5		ENSP00000359765.1
ADGRL2	ENST00000370721.5	c.86C>T	p.Ala29Val	missense_variant	6/25	5		ENSP00000359756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726682

Gnomad4 AFR exome AF: 0.000149

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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

Oct 01, 2024

The c.86C>T (p.A29V) alteration is located in exon 3 (coding exon 2) of the ADGRL2 gene. This alteration results from a C to T substitution at nucleotide position 86, causing the alanine (A) at amino acid position 29 to be replaced by a valine (V). 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	0.74
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	.;T;.;.;D;.;.;.;.;.;T;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;D;.;D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99	.;.;.;.;.;.;D;D;D;D;.;.
Vest4		0.45
MutPred		0.59		Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);
MVP		0.082
MPC		1.5
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.53
gMVP		0.70

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: rs2094597932; hg19: chr1-82372714;