chr1-81907037-C-G

Position:

• chr1-81907037-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001366006.2(ADGRL2):​c.94C>G​(p.Pro32Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., 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: 7.81

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 -4 ACMG points.

• 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.94C>G	p.Pro32Ala	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.94C>G	p.Pro32Ala	missense_variant	3/24		NM_001366006.2	ENSP00000509478.1
ADGRL2	ENST00000370725.5	c.94C>G	p.Pro32Ala	missense_variant	6/26	5		ENSP00000359760.1
ADGRL2	ENST00000370723.5	c.94C>G	p.Pro32Ala	missense_variant	6/25	5		ENSP00000359758.1
ADGRL2	ENST00000370728.5	c.94C>G	p.Pro32Ala	missense_variant	6/25	5		ENSP00000359763.1
ADGRL2	ENST00000370727.5	c.94C>G	p.Pro32Ala	missense_variant	6/25	5		ENSP00000359762.1
ADGRL2	ENST00000370730.5	c.94C>G	p.Pro32Ala	missense_variant	6/24	5		ENSP00000359765.1
ADGRL2	ENST00000370721.5	c.94C>G	p.Pro32Ala	missense_variant	6/25	5		ENSP00000359756.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727076

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Jun 24, 2022

The c.94C>G (p.P32A) alteration is located in exon 3 (coding exon 2) of the ADGRL2 gene. This alteration results from a C to G substitution at nucleotide position 94, causing the proline (P) at amino acid position 32 to be replaced by an alanine (A). 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	0.86
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.;.;D;.;.;.;.;.;T;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;.;.;.;D;D;D;D;.;.
Vest4		0.64
MutPred		0.67		Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);Gain of catalytic residue at P32 (P = 0.1082);
MVP		0.093
MPC		1.7
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.56
gMVP		0.73

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: rs2094597982; hg19: chr1-82372722;