14-46957483-C-G

Variant names:

• chr14-46957483-C-G
• rs76888297
• NM_001113498.3:c.1980G>C

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 4 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDGA2	NM_001113498.3	c.1980G>C	p.Gln660His	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.1980G>C	p.Gln660His	missense_variant	Exon 9 of 17	1	NM_001113498.3	ENSP00000382178.4
MDGA2	ENST00000357362.7	c.1086G>C	p.Gln362His	missense_variant	Exon 9 of 17	5		ENSP00000349925.3
MDGA2	ENST00000557238.5	n.*358G>C		non_coding_transcript_exon_variant	Exon 9 of 14	5		ENSP00000452593.1
MDGA2	ENST00000557238.5	n.*358G>C		3_prime_UTR_variant	Exon 9 of 14	5		ENSP00000452593.1

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

GnomAD2 exomes AF: 0.00204 AC: 510 AN: 249480 AF XY: 0.00177

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 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

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0265 AC: 1052 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111992

Other (OTH) AF: 0.00147 AC: 89 AN: 60396

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

African (AFR) AF: 0.000457 AC: 19 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0227 AC: 117 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

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

Feb 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
DEOGEN2	Benign	0.017	.;.;T
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
MutationAssessor	Benign	1.8	.;.;L
PhyloP100		-0.32
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.11	T;T;.
Sift4G	Benign	0.067	.;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
Mutation Taster		=97/3	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: rs76888297; hg19: chr14-47426686;