14-46957472-T-C

Variant names:

• chr14-46957472-T-C
• rs1885606889
• NM_001113498.3:c.1991A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001113498.3(MDGA2):​c.1991A>G​(p.Glu664Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDGA2 NM_001113498.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44
• Publications: 0 publications found

Genes affected

MDGA2 (HGNC:19835): (MAM domain containing glycosylphosphatidylinositol anchor 2) Predicted to be involved in regulation of presynapse assembly; regulation of synaptic membrane adhesion; and spinal cord motor neuron differentiation. Predicted to act upstream of or within neuron migration and pattern specification process. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in GABA-ergic synapse and glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
MDGA2	NM_001113498.3	c.1991A>G	p.Glu664Gly	missense_variant	Exon 9 of 17	ENST00000399232.8	NP_001106970.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDGA2	ENST00000399232.8	c.1991A>G	p.Glu664Gly	missense_variant	Exon 9 of 17	1	NM_001113498.3	ENSP00000382178.4
MDGA2	ENST00000357362.7	c.1097A>G	p.Glu366Gly	missense_variant	Exon 9 of 17	5		ENSP00000349925.3
MDGA2	ENST00000557238.5	n.*369A>G		non_coding_transcript_exon_variant	Exon 9 of 14	5		ENSP00000452593.1
MDGA2	ENST00000557238.5	n.*369A>G		3_prime_UTR_variant	Exon 9 of 14	5		ENSP00000452593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1784A>G (p.K595R) alteration is located in exon 8 (coding exon 8) of the MDGA2 gene. This alteration results from a A to G substitution at nucleotide position 1784, causing the lysine (K) at amino acid position 595 to be replaced by an arginine (R). 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	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	.;.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;.;M
PhyloP100		7.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.031	.;D;.
Polyphen		0.79	.;.;P
Vest4		0.74
MutPred		0.34		.;.;Loss of stability (P = 0.0186);
MVP		0.58
MPC		0.32
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.75
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1885606889; hg19: chr14-47426675;