19-12657507-G-C

Position:

• chr19-12657507-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000528.4(MAN2B1):​c.1358C>G​(p.Ser453Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,417,662 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S453F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 60) in uniprot entity MA2B1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000528.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12657507-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.1358C>G	p.Ser453Cys	missense_variant	11/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.1355C>G	p.Ser452Cys	missense_variant	11/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.1361C>G	p.Ser454Cys	missense_variant	11/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.257C>G	p.Ser86Cys	missense_variant	4/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.1358C>G	p.Ser453Cys	missense_variant	11/24	1	NM_000528.4	ENSP00000395473.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417662 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 701580

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.80	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.25
MutPred		0.82		Loss of disorder (P = 0.0057);.;
MVP		0.89
MPC		0.60
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.28
gMVP		0.71

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: rs864621984; hg19: chr19-12768321;