Variant 9-70108408-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_153267.5(MAMDC2):c.346T>C(p.Trp116Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,096 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

MAMDC2
NM_153267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.32

Variant links:

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 links:

MAMDC2 (HGNC:):

MAMDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAMDC2	NM_153267.5 linkuse as main transcript	c.346T>C	p.Trp116Arg	missense_variant	3/14	ENST00000377182.5	NP_694999.3
MAMDC2	NM_001347990.2 linkuse as main transcript	c.346T>C	p.Trp116Arg	missense_variant	3/12		NP_001334919.1
MAMDC2	NR_125850.1 linkuse as main transcript	n.963T>C		non_coding_transcript_exon_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAMDC2	ENST00000377182.5 linkuse as main transcript	c.346T>C	p.Trp116Arg	missense_variant	3/14	1	NM_153267.5	ENSP00000366387.4	Q7Z304-1
MAMDC2-AS1	ENST00000414515.7 linkuse as main transcript	n.106+5347A>G		intron_variant		5
MAMDC2-AS1	ENST00000591368.5 linkuse as main transcript	n.651+800A>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00123

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000606

AC:

152

AN:

250844

Hom.:

AF XY:

0.000575

AC XY:

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.00125

AC:

1831

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

865

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.00158

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000689

AC:

105

AN:

152358

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000729

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000560

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.000950

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.346T>C (p.W116R) alteration is located in exon 3 (coding exon 3) of the MAMDC2 gene. This alteration results from a T to C substitution at nucleotide position 346, causing the tryptophan (W) at amino acid position 116 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.080

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.80

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

0.85

Vest4

0.96

MutPred

0.76

Gain of disorder (P = 0.0014);

MVP

0.56

MPC

0.32

ClinPred

0.12

GERP RS

5.9

Varity_R

0.87

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over