Variant 9-70108217-A-G 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.155A>G(p.Tyr52Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,586,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MAMDC2
NM_153267.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.99

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

MAMDC2-AS1 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
MAMDC2	NM_153267.5 linkuse as main transcript	c.155A>G	p.Tyr52Cys	missense_variant	3/14	ENST00000377182.5
MAMDC2	NM_001347990.2 linkuse as main transcript	c.155A>G	p.Tyr52Cys	missense_variant	3/12
MAMDC2	NR_125850.1 linkuse as main transcript	n.772A>G		non_coding_transcript_exon_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAMDC2	ENST00000377182.5 linkuse as main transcript	c.155A>G	p.Tyr52Cys	missense_variant	3/14	1	NM_153267.5	P1	Q7Z304-1
MAMDC2-AS1	ENST00000591368.5 linkuse as main transcript	n.651+991T>C		intron_variant, non_coding_transcript_variant		5
MAMDC2-AS1	ENST00000414515.7 linkuse as main transcript	n.106+5538T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

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

GnomAD3 exomes

AF:

0.0000827

AC:

AN:

229774

Hom.:

AF XY:

0.0000806

AC XY:

AN XY:

124060

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00109

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:

0.0000119

AC:

AN:

1433930

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

711038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000435

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

AF:

0.0000263

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000988

AC:

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

Jul 11, 2023

The c.155A>G (p.Y52C) alteration is located in exon 3 (coding exon 3) of the MAMDC2 gene. This alteration results from a A to G substitution at nucleotide position 155, causing the tyrosine (Y) at amino acid position 52 to be replaced by a cysteine (C). 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

0.65

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.4

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.82

MutPred

0.69

Loss of phosphorylation at Y52 (P = 0.0218);

MVP

0.60

MPC

0.61

ClinPred

0.46

GERP RS

5.9

Varity_R

0.45

gMVP

0.89

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