rs754036398

Variant names:

• chr19-12665505-C-G
• rs754036398
• NM_000528.4:c.283G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-12665505-C-G
• chr19-12665505-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000528.4(MAN2B1):​c.283G>C​(p.Ala95Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. A95A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.36
• Publications: 5 publications found

Genes affected

MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

MAN2B1 Gene-Disease associations (from GenCC):

• alpha-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ENSG00000269590 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.283G>C	p.Ala95Pro	missense_variant	Exon 3 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001440570.1	c.283G>C	p.Ala95Pro	missense_variant	Exon 3 of 24		NP_001427499.1
MAN2B1	NM_001173498.2	c.283G>C	p.Ala95Pro	missense_variant	Exon 3 of 24		NP_001166969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.283G>C	p.Ala95Pro	missense_variant	Exon 3 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269590	ENST00000597961.1	c.274G>C	p.Ala92Pro	missense_variant	Exon 4 of 5	4		ENSP00000472710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:1

Jun 07, 2012

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M;M;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D;D;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.94	P;.;.;.
Vest4		0.92
MutPred		0.75		Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;.;
MVP		0.88
MPC		1.5
ClinPred		0.96	D
GERP RS		3.6
Varity_R		0.81
gMVP		0.95
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs754036398; hg19: chr19-12776319;