Genetic Variant AMIGO2:p.Arg465Lys (chr12-47077609-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001370299.1(AMIGO2):c.1394G>A(p.Arg465Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,890 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: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

AMIGO2
NM_001370299.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.01

Variant links:

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]

AMIGO2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2557972).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMIGO2	NM_001370299.1 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 3 of 3	ENST00000550413.2	NP_001357228.1
AMIGO2	NM_001143668.1 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 3 of 3		NP_001137140.1	Q86SJ2A0A024R127
AMIGO2	NM_181847.4 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 2 of 2		NP_862830.1	Q86SJ2A0A024R127
AMIGO2	XM_047428785.1 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 2 of 2		XP_047284741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AMIGO2	ENST00000550413.2 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 3 of 3	1	NM_001370299.1	ENSP00000449034.1	Q86SJ2
AMIGO2	ENST00000266581.4 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 2 of 2	1		ENSP00000266581.4	Q86SJ2
AMIGO2	ENST00000429635.1 link	c.1394G>A	p.Arg465Lys	missense_variant	Exon 3 of 3	1		ENSP00000406020.1	Q86SJ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251464

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00000342

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1394G>A (p.R465K) 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 1394, causing the arginine (R) at amino acid position 465 to be replaced by a lysine (K). 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

0.19

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

T;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.80

.;.;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.83

N;N;N

REVEL

Benign

0.097

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.95

P;P;P

Vest4

0.16

MutPred

0.42

Gain of catalytic residue at A462 (P = 0.0025);Gain of catalytic residue at A462 (P = 0.0025);Gain of catalytic residue at A462 (P = 0.0025);

MVP

0.62

MPC

1.2

ClinPred

0.91

GERP RS

5.1

Varity_R

0.28

gMVP

0.48

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