9-70044677-C-T

Variant names:

• chr9-70044677-C-T
• NM_153267.5:c.128C>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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

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)

ACMG classification

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
MAMDC2	NM_153267.5	c.128C>T	p.Pro43Leu	missense_variant	Exon 2 of 14	ENST00000377182.5	NP_694999.3
MAMDC2	NM_001347990.2	c.128C>T	p.Pro43Leu	missense_variant	Exon 2 of 12		NP_001334919.1
MAMDC2	NR_125850.1	n.745C>T		non_coding_transcript_exon_variant	Exon 2 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAMDC2	ENST00000377182.5	c.128C>T	p.Pro43Leu	missense_variant	Exon 2 of 14	1	NM_153267.5	ENSP00000366387.4
MAMDC2-AS1	ENST00000628563.2	n.199-10478G>A		intron_variant	Intron 2 of 2	5
MAMDC2-AS1	ENST00000629922.2	n.300-10478G>A		intron_variant	Intron 3 of 3	5
MAMDC2-AS1	ENST00000630191.2	n.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

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;