Variant 9-70126278-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_153267.5(MAMDC2):c.763C>A(p.Gln255Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MAMDC2
NM_153267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.76

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4033125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAMDC2	NM_153267.5 linkuse as main transcript	c.763C>A	p.Gln255Lys	missense_variant	6/14	ENST00000377182.5	NP_694999.3
MAMDC2	NM_001347990.2 linkuse as main transcript	c.763C>A	p.Gln255Lys	missense_variant	6/12		NP_001334919.1
MAMDC2	NR_125850.1 linkuse as main transcript	n.1380C>A		non_coding_transcript_exon_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAMDC2	ENST00000377182.5 linkuse as main transcript	c.763C>A	p.Gln255Lys	missense_variant	6/14	1	NM_153267.5	ENSP00000366387.4		Q7Z304-1
MAMDC2-AS1	ENST00000591368.5 linkuse as main transcript	n.409-12418G>T		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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 20, 2024

The c.763C>A (p.Q255K) alteration is located in exon 6 (coding exon 6) of the MAMDC2 gene. This alteration results from a C to A substitution at nucleotide position 763, causing the glutamine (Q) at amino acid position 255 to be replaced by a lysine (K). 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

Benign

0.076

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0062

Eigen

Benign

0.057

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.73

M_CAP

Benign

0.010

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Benign

0.42

Sift4G

Uncertain

0.014

Polyphen

0.66

Vest4

0.34

MutPred

0.77

Gain of solvent accessibility (P = 0.0038);

MVP

0.26

MPC

0.15

ClinPred

0.25

GERP RS

4.2

Varity_R

0.39

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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