dbSNP rs776057039: MAMDC2:p.Ala40Thr (chr9-70044667-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153267.5(MAMDC2):c.118G>A(p.Ala40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,399,364 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MAMDC2
NM_153267.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.844

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039374202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MAMDC2	NM_153267.5 link	c.118G>A	p.Ala40Thr	missense_variant	Exon 2 of 14	ENST00000377182.5	NP_694999.3
MAMDC2	NM_001347990.2 link	c.118G>A	p.Ala40Thr	missense_variant	Exon 2 of 12		NP_001334919.1
MAMDC2	NR_125850.1 link	n.735G>A		non_coding_transcript_exon_variant	Exon 2 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAMDC2	ENST00000377182.5 link	c.118G>A	p.Ala40Thr	missense_variant	Exon 2 of 14	1	NM_153267.5	ENSP00000366387.4	Q7Z304-1
MAMDC2-AS1	ENST00000628563.2 link	n.199-10468C>T		intron_variant	Intron 2 of 2	5
MAMDC2-AS1	ENST00000629922.2 link	n.300-10468C>T		intron_variant	Intron 3 of 3	5
MAMDC2-AS1	ENST00000630191.2 link	n.396-10468C>T		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000639

AC:

AN:

156582

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82340

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000883

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:

0.0000100

AC:

AN:

1399364

Hom.:

Cov.:

AF XY:

0.0000130

AC XY:

AN XY:

690196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000392

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0056

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.63

M_CAP

Benign

0.0063

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.34

PrimateAI

Benign

0.32

PROVEAN

Benign

0.18

REVEL

Benign

0.051

Sift

Benign

0.51

Sift4G

Benign

0.50

Polyphen

0.0010

Vest4

0.039

MutPred

0.45

Loss of relative solvent accessibility (P = 0.0676);

MVP

0.20

MPC

0.11

ClinPred

0.034

GERP RS

-0.32

Varity_R

0.073

gMVP

0.35

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over