19-12664832-G-C

Variant names:

• chr19-12664832-G-C
• rs864621977
• NM_000528.4:c.590C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000528.4(MAN2B1):​c.590C>G​(p.Pro197Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• 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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 19-12664832-G-C is Pathogenic according to our data. Variant chr19-12664832-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12664832-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.590C>G	p.Pro197Arg	missense_variant	Exon 4 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.590C>G	p.Pro197Arg	missense_variant	Exon 4 of 24		NP_001166969.1
MAN2B1	XM_005259913.3	c.590C>G	p.Pro197Arg	missense_variant	Exon 4 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.590C>G	p.Pro197Arg	missense_variant	Exon 4 of 24	1	NM_000528.4	ENSP00000395473.2
ENSG00000269590	ENST00000597961.1	c.581C>G	p.Pro194Arg	missense_variant	Exon 5 of 5	4		ENSP00000472710.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461532 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Pathogenic:3 Uncertain:1

Apr 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MAN2B1 c.590C>G (p.Pro197Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 244732 control chromosomes. c.590C>G has been reported in the literature in an individual affected with Alpha-Mannosidosis (Borgwardt_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in regards to intracellular processing and secretion into the medium in transfected cells, indicating an inactive protein (Kuokkanen_2011, Stensland_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26048034, 21505070, 22161967, 25762455). ClinVar contains an entry for this variant (Variation ID: 208254). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 07, 2012

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 22, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 14, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.590C>G (p.P197R) alteration is located in exon 4 (coding exon 4) of the MAN2B1 gene. This alteration results from a C to G substitution at nucleotide position 590, causing the proline (P) at amino acid position 197 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in conjunction with a second MAN2B1 alteration in a patient with alpha-mannosidosis (Riise Stensland, 2012). This amino acid position is highly conserved in available vertebrate species. In vitro studies demonstrate that this alteration results in an inactive protein with less than 20% of wild type activity in multiple cell types (Riise Stensland, 2012). Additionally, studies in transfected cells show that p.Pro197Arg is not processed and retained in the ER in HeLa cells, although COS-7 cells showed dissimilar localization (Kuokkanen, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.7	H;H;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.8	D;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.94		Gain of MoRF binding (P = 0.0756);Gain of MoRF binding (P = 0.0756);.;
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.97

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;