1-81943763-G-A

Position:

chr1-81943763-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001366006.2(ADGRL2):c.1204G>A(p.Ala402Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,611,268 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ADGRL2
NM_001366006.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.52

Variant links:

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]

ADGRL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042968124).

BS2

High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL2	NM_001366006.2 link	c.1204G>A	p.Ala402Thr	missense_variant	6/24	ENST00000686636.1	NP_001352935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRL2	ENST00000686636.1 link	c.1204G>A	p.Ala402Thr	missense_variant	6/24		NM_001366006.2	ENSP00000509478.1	A0A8I5KUX3
ADGRL2	ENST00000370725.5 link	c.1192G>A	p.Ala398Thr	missense_variant	8/26	5		ENSP00000359760.1	O95490-6
ADGRL2	ENST00000370723.5 link	c.1192G>A	p.Ala398Thr	missense_variant	8/25	5		ENSP00000359758.1	O95490-7
ADGRL2	ENST00000370728.5 link	c.1192G>A	p.Ala398Thr	missense_variant	8/25	5		ENSP00000359763.1	O95490-1
ADGRL2	ENST00000370727.5 link	c.1192G>A	p.Ala398Thr	missense_variant	8/25	5		ENSP00000359762.1	B1ALU3
ADGRL2	ENST00000370730.5 link	c.1192G>A	p.Ala398Thr	missense_variant	8/24	5		ENSP00000359765.1	O95490-5
ADGRL2	ENST00000370721.5 link	c.1204G>A	p.Ala402Thr	missense_variant	9/25	5		ENSP00000359756.1	B1ALU1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000840

AC:

AN:

249862

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1459364

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

725766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000454

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74214

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.000115

AC:

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

Jun 07, 2023

The c.1192G>A (p.A398T) alteration is located in exon 5 (coding exon 4) of the ADGRL2 gene. This alteration results from a G to A substitution at nucleotide position 1192, causing the alanine (A) at amino acid position 398 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

Benign

0.15

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Benign

0.012

.;T;.;.;T;.;.;.;.;.;T;T

Eigen

Benign

0.069

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;.;D;D;.;D;.;D;D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.043

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.98

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.82

N;N;N;N;N;N;N;N;N;N;.;N

REVEL

Benign

0.14

Sift

Benign

0.41

T;T;T;T;T;T;T;T;T;T;.;T

Sift4G

Benign

0.55

T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.028, 0.11, 0.013

.;.;.;.;.;.;B;B;B;B;.;.

Vest4

0.64

MutPred

0.23

.;Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);Gain of glycosylation at A398 (P = 8e-04);

MVP

0.068

MPC

0.46

ClinPred

0.22

GERP RS

5.7

Varity_R

0.12

gMVP

0.26

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