14-46957434-C-T

Variant names:

• chr14-46957434-C-T
• rs12590500
• NM_001113498.3:c.2029G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001113498.3(MDGA2):​c.2029G>A​(p.Val677Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MDGA2 NM_001113498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16238597).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113498.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDGA2	NM_001113498.3	MANE Select	c.2029G>A	p.Val677Ile	missense	Exon 9 of 17	NP_001106970.4	Q7Z553-3
	MDGA2	NM_182830.4		c.1135G>A	p.Val379Ile	missense	Exon 9 of 17	NP_878250.2	Q7Z553-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDGA2	ENST00000399232.8	TSL:1 MANE Select	c.2029G>A	p.Val677Ile	missense	Exon 9 of 17	ENSP00000382178.4	Q7Z553-3
	MDGA2	ENST00000357362.7	TSL:5	c.1135G>A	p.Val379Ile	missense	Exon 9 of 17	ENSP00000349925.3	Q7Z553-2
	MDGA2	ENST00000557238.5	TSL:5	n.*407G>A		non_coding_transcript_exon	Exon 9 of 14	ENSP00000452593.1	G3V5Z1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.053
Sift	Benign	0.19	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.35		Gain of catalytic residue at S612 (P = 0.001)
MVP		0.35
MPC		0.14
ClinPred		0.11	T
GERP RS		4.3
Varity_R		0.053
gMVP		0.34
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs12590500; hg19: chr14-47426637;