rs193920950

chr9-70044607-G-Achr9-70044607-G-Cchr9-70044607-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153267.5(MAMDC2):c.58G>A(p.Asp20Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,550,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: MAMDC2 NM_153267.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.47

Genes affected

MAMDC2 (HGNC:23673): (MAM domain containing 2) Predicted to enable glycosaminoglycan binding activity. Predicted to act upstream of or within peptide cross-linking via chondroitin 4-sulfate glycosaminoglycan. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

MAMDC2-AS1 (HGNC:48719): (MAMDC2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11021212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAMDC2	NM_153267.5	c.58G>A	p.Asp20Asn	missense_variant	2/14	ENST00000377182.5
MAMDC2	NM_001347990.2	c.58G>A	p.Asp20Asn	missense_variant	2/12
MAMDC2	NR_125850.1	n.675G>A		non_coding_transcript_exon_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAMDC2	ENST00000377182.5	c.58G>A	p.Asp20Asn	missense_variant	2/14	1	NM_153267.5	P1
MAMDC2-AS1	ENST00000628563.2	n.199-10408C>T		intron_variant, non_coding_transcript_variant		5
MAMDC2-AS1	ENST00000629922.2	n.300-10408C>T		intron_variant, non_coding_transcript_variant		5
MAMDC2-AS1	ENST00000630191.2	n.396-10408C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1398470 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 689770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000742

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.50	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.068
Sift	Benign	0.076	T
Sift4G	Uncertain	0.054	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.41		Loss of loop (P = 0.0374);
MVP		0.32
MPC		0.11
ClinPred		0.52	D
GERP RS		4.4
Varity_R		0.12
gMVP		0.45

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: rs193920950; hg19: chr9-72659523; COSMIC: COSV65860952;