chr1-81936728-G-T

Position:

• chr1-81936728-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001366006.2(ADGRL2):​c.288G>T​(p.Arg96Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADGRL2 NM_001366006.2 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL2	NM_001366006.2	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	4/24	ENST00000686636.1	NP_001352935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL2	ENST00000686636.1	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	4/24		NM_001366006.2	ENSP00000509478.1
ADGRL2	ENST00000370725.5	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	7/26	5		ENSP00000359760.1
ADGRL2	ENST00000370723.5	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	7/25	5		ENSP00000359758.1
ADGRL2	ENST00000370728.5	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	7/25	5		ENSP00000359763.1
ADGRL2	ENST00000370727.5	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	7/25	5		ENSP00000359762.1
ADGRL2	ENST00000370730.5	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	7/24	5		ENSP00000359765.1
ADGRL2	ENST00000370721.5	c.288G>T	p.Arg96Ser	missense_variant, splice_region_variant	7/25	5		ENSP00000359756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1394050 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 693604

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jun 24, 2022

The c.288G>T (p.R96S) alteration is located in exon 4 (coding exon 3) of the ADGRL2 gene. This alteration results from a G to T substitution at nucleotide position 288, causing the arginine (R) at amino acid position 96 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	.;T;.;.;T;.;.;.;.;.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D;.;D;.;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.2	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.30
Sift	Benign	0.089	T;D;D;D;D;D;D;D;D;D;.;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.88, 1.0, 0.76	.;.;.;.;.;.;P;D;P;P;.;.
Vest4		0.86
MutPred		0.67		Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.34
MPC		1.6
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.67
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.010		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: rs747123560; hg19: chr1-82402412;