rs12590500

Positions:

• chr14-46957434-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001113498.3(MDGA2):​c.2029G>T​(p.Val677Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,613,874 control chromosomes in the GnomAD database, including 6,663 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 𝑓 0.12 (2000 hom., cov: 32)
  • Exomes 𝑓: 0.048 (4663 hom.)
• Consequence: MDGA2 NM_001113498.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047100484).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDGA2	NM_001113498.3	c.2029G>T	p.Val677Phe	missense_variant	9/17	ENST00000399232.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDGA2	ENST00000399232.8	c.2029G>T	p.Val677Phe	missense_variant	9/17	1	NM_001113498.3	P1
MDGA2	ENST00000357362.7	c.1135G>T	p.Val379Phe	missense_variant	9/17	5
MDGA2	ENST00000557238.5	c.*407G>T		3_prime_UTR_variant, NMD_transcript_variant	9/14	5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17825 AN: 151956 Hom.: 1979 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0937

GnomAD3 exomes AF: 0.0960 AC: 23935 AN: 249318 Hom.: 2567 AF XY: 0.0843 AC XY: 11400 AN XY: 135260

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.0375

Gnomad EAS exome AF: 0.114

Gnomad SAS exome AF: 0.0948

Gnomad FIN exome AF: 0.0474

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0719

GnomAD4 exome AF: 0.0479 AC: 70048 AN: 1461800 Hom.: 4663 Cov.: 31 AF XY: 0.0474 AC XY: 34457 AN XY: 727206

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.0390

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.0912

Gnomad4 FIN exome AF: 0.0478

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0620

GnomAD4 genome AF: 0.118 AC: 17899 AN: 152074 Hom.: 2000 Cov.: 32 AF XY: 0.121 AC XY: 8990 AN XY: 74328

Gnomad4 AFR AF: 0.267

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0951

Alfa AF: 0.0462 Hom.: 1036

Bravo AF: 0.138

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0226 AC: 87

ESP6500AA AF: 0.253 AC: 941

ESP6500EA AF: 0.0233 AC: 191

ExAC AF: 0.0893 AC: 10792

Asia WGS AF: 0.150 AC: 519 AN: 3478

EpiCase AF: 0.0248

EpiControl AF: 0.0212

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.90	P;P;P;P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.037
Sift	Benign	0.051	T;D;.
Polyphen		0.21	.;.;B
Vest4		0.15
MPC		0.25
ClinPred		0.0085	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.60

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: rs12590500; hg19: chr14-47426637; COSMIC: COSV62099247; COSMIC: COSV62099247;