12-47077496-T-C

Variant names:

• chr12-47077496-T-C
• NM_001370299.1:c.1507A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001370299.1(AMIGO2):​c.1507A>G​(p.Lys503Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 7.50

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMIGO2	NM_001370299.1	c.1507A>G	p.Lys503Glu	missense_variant	Exon 3 of 3	ENST00000550413.2	NP_001357228.1
AMIGO2	NM_001143668.1	c.1507A>G	p.Lys503Glu	missense_variant	Exon 3 of 3		NP_001137140.1
AMIGO2	NM_181847.4	c.1507A>G	p.Lys503Glu	missense_variant	Exon 2 of 2		NP_862830.1
AMIGO2	XM_047428785.1	c.1507A>G	p.Lys503Glu	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.1507A>G	p.Lys503Glu	missense_variant	Exon 3 of 3	1	NM_001370299.1	ENSP00000449034.1
AMIGO2	ENST00000266581.4	c.1507A>G	p.Lys503Glu	missense_variant	Exon 2 of 2	1		ENSP00000266581.4
AMIGO2	ENST00000429635.1	c.1507A>G	p.Lys503Glu	missense_variant	Exon 3 of 3	1		ENSP00000406020.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461840 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1507A>G (p.K503E) alteration is located in exon 2 (coding exon 1) of the AMIGO2 gene. This alteration results from a A to G substitution at nucleotide position 1507, causing the lysine (K) at amino acid position 503 to be replaced by a glutamic acid (E). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	.;.;T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.086	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.53
MutPred		0.33		Loss of ubiquitination at K503 (P = 0.0017);Loss of ubiquitination at K503 (P = 0.0017);Loss of ubiquitination at K503 (P = 0.0017);
MVP		0.80
MPC		1.5
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.20
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-47471279;