9-70044677-C-T

Variant summary

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

The NM_153267.5(MAMDC2):​c.128C>T​(p.Pro43Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MAMDC2
NM_153267.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.46
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-AS1 (HGNC:48719): (MAMDC2 antisense RNA 1)

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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 rank MANE Protein UniProt
MAMDC2NM_153267.5 linkc.128C>T p.Pro43Leu missense_variant Exon 2 of 14 ENST00000377182.5 NP_694999.3
MAMDC2NM_001347990.2 linkc.128C>T p.Pro43Leu missense_variant Exon 2 of 12 NP_001334919.1
MAMDC2NR_125850.1 linkn.745C>T non_coding_transcript_exon_variant Exon 2 of 14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAMDC2ENST00000377182.5 linkc.128C>T p.Pro43Leu missense_variant Exon 2 of 14 1 NM_153267.5 ENSP00000366387.4 Q7Z304-1
MAMDC2-AS1ENST00000628563.2 linkn.199-10478G>A intron_variant Intron 2 of 2 5
MAMDC2-AS1ENST00000629922.2 linkn.300-10478G>A intron_variant Intron 3 of 3 5
MAMDC2-AS1ENST00000630191.2 linkn.396-10478G>A intron_variant Intron 4 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.128C>T (p.P43L) alteration is located in exon 2 (coding exon 2) of the MAMDC2 gene. This alteration results from a C to T substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a leucine (L). 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
0.16
BayesDel_addAF
Benign
0.0082
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.019
T
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.82
T
M_CAP
Benign
0.013
T
MetaRNN
Uncertain
0.51
D
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.6
D
REVEL
Benign
0.17
Sift
Benign
0.039
D
Sift4G
Benign
0.16
T
Polyphen
0.92
P
Vest4
0.51
MutPred
0.55
Loss of loop (P = 0.0512);
MVP
0.57
MPC
0.49
ClinPred
0.96
D
GERP RS
5.6
Varity_R
0.14
gMVP
0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-72659593; API