12-47077915-C-T

Variant names:

• chr12-47077915-C-T
• rs756839239
• NM_001370299.1:c.1088G>A

Variant summary

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

The NM_001370299.1(AMIGO2):​c.1088G>A​(p.Cys363Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,724 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: 6.8e-7 (0 hom.)
• Consequence: AMIGO2 NM_001370299.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

Genes affected

AMIGO2 (HGNC:24073): (adhesion molecule with Ig like domain 2) Predicted to be involved in several processes, including heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; homophilic cell adhesion via plasma membrane adhesion molecules; and negative regulation of programmed cell death. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be located in nucleus and plasma membrane. Predicted to be integral component of membrane. Biomarker of gastric adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMIGO2	NM_001370299.1	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 3 of 3	ENST00000550413.2	NP_001357228.1
AMIGO2	NM_001143668.1	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 3 of 3		NP_001137140.1
AMIGO2	NM_181847.4	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 2 of 2		NP_862830.1
AMIGO2	XM_047428785.1	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 2 of 2		XP_047284741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMIGO2	ENST00000550413.2	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 3 of 3	1	NM_001370299.1	ENSP00000449034.1
AMIGO2	ENST00000266581.4	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 2 of 2	1		ENSP00000266581.4
AMIGO2	ENST00000429635.1	c.1088G>A	p.Cys363Tyr	missense_variant	Exon 3 of 3	1		ENSP00000406020.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251376 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461724 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1088G>A (p.C363Y) alteration is located in exon 2 (coding exon 1) of the AMIGO2 gene. This alteration results from a G to A substitution at nucleotide position 1088, causing the cysteine (C) at amino acid position 363 to be replaced by a tyrosine (Y). 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	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;.;T
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	4.0	H;H;H
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.1	D;D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.94
MutPred		0.86		Gain of catalytic residue at V360 (P = 0);Gain of catalytic residue at V360 (P = 0);Gain of catalytic residue at V360 (P = 0);
MVP		0.85
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.99

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: rs756839239; hg19: chr12-47471698;