rs864621977

Positions:

• chr19-12664832-G-A
• chr19-12664832-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000528.4(MAN2B1):​c.590C>T​(p.Pro197Leu) 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. 12/21 in silico tools predict a damaging 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. P197R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.37

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]

ENSG00000269590 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12664832-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.590C>T	p.Pro197Leu	missense_variant	4/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.590C>T	p.Pro197Leu	missense_variant	4/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.590C>T	p.Pro197Leu	missense_variant	4/24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.590C>T	p.Pro197Leu	missense_variant	4/24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269590	ENST00000597961.1	c.581C>T	p.Pro194Leu	missense_variant	5/5	4		ENSP00000472710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.7	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-9.8	D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.93		Loss of disorder (P = 0.0594);Loss of disorder (P = 0.0594);.;
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.94

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

Other links and lift over

dbSNP: rs864621977; hg19: chr19-12775646; COSMIC: COSV54419463; COSMIC: COSV54419463;