15-75358495-G-C

Variant names:

• chr15-75358495-G-C
• rs1128933
• NM_006715.4:c.2370C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006715.4(MAN2C1):​c.2370C>G​(p.Asp790Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D790H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAN2C1 NM_006715.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410
• Publications: 20 publications found

Genes affected

MAN2C1 (HGNC:6827): (mannosidase alpha class 2C member 1) Predicted to enable alpha-mannosidase activity. Predicted to be involved in oligosaccharide catabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MAN2C1 Gene-Disease associations (from GenCC):

• congenital disorder of deglycosylation 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
MAN2C1	NM_006715.4	c.2370C>G	p.Asp790Glu	missense_variant	Exon 20 of 26	ENST00000267978.10	NP_006706.2
MAN2C1	NM_001256494.2	c.2421C>G	p.Asp807Glu	missense_variant	Exon 20 of 26		NP_001243423.1
MAN2C1	NM_001256495.2	c.2370C>G	p.Asp790Glu	missense_variant	Exon 20 of 26		NP_001243424.1
MAN2C1	NM_001256496.2	c.2073C>G	p.Asp691Glu	missense_variant	Exon 18 of 24		NP_001243425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2C1	ENST00000267978.10	c.2370C>G	p.Asp790Glu	missense_variant	Exon 20 of 26	1	NM_006715.4	ENSP00000267978.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.20	.;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.7	L;.;.;L;.
PhyloP100		-0.041
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N;N;N;N;.
REVEL	Uncertain	0.50
Sift	Benign	0.20	T;T;T;T;.
Sift4G	Benign	0.39	T;T;T;T;T
Polyphen		0.99	.;.;.;D;.
Vest4		0.63
MutPred		0.48		Loss of catalytic residue at C793 (P = 0.1823);.;.;Loss of catalytic residue at C793 (P = 0.1823);.;
MVP		0.17
MPC		0.29
ClinPred		0.81	D
GERP RS		-7.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.38
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1128933; hg19: chr15-75650836;