14-46957483-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001113498.3(MDGA2):c.1980G>C(p.Gln660His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000807 in 1,614,084 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00091 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (19 hom.)
• Consequence: MDGA2 NM_001113498.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.319

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026649833).
• BP6: Variant 14-46957483-C-G is Benign according to our data. Variant chr14-46957483-C-G is described in ClinVar as [Benign]. Clinvar id is 729728.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000907 (138/152212) while in subpopulation EAS AF= 0.0227 (117/5158). AF 95% confidence interval is 0.0193. There are 2 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDGA2	NM_001113498.3	c.1980G>C	p.Gln660His	missense_variant	9/17	ENST00000399232.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDGA2	ENST00000399232.8	c.1980G>C	p.Gln660His	missense_variant	9/17	1	NM_001113498.3	P1
MDGA2	ENST00000357362.7	c.1086G>C	p.Gln362His	missense_variant	9/17	5
MDGA2	ENST00000557238.5	c.*358G>C		3_prime_UTR_variant, NMD_transcript_variant	9/14	5

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 152094 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00204 AC: 510 AN: 249480 Hom.: 10 AF XY: 0.00177 AC XY: 240 AN XY: 135332

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0273

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000796 AC: 1164 AN: 1461872 Hom.: 19 Cov.: 31 AF XY: 0.000727 AC XY: 529 AN XY: 727238

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0265

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000907 AC: 138 AN: 152212 Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74408

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0227

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000867 Hom.: 0

Bravo AF: 0.00122

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00189 AC: 228

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Uncertain	1.0
Eigen	Benign	0.097
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.86	D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;.
Polyphen		0.91	.;.;P
Vest4		0.26
MutPred		0.31		.;.;Gain of catalytic residue at F588 (P = 0.0196);
MVP		0.26
MPC		0.17
ClinPred		0.031	T
GERP RS		2.1
Varity_R		0.069
gMVP		0.50

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: rs76888297; hg19: chr14-47426686;