rs117843968

chr19-12663723-G-Achr19-12663723-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000528.4(MAN2B1):c.743C>T(p.Pro248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,612,812 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P248R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (27 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.35

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03565052).
• BP6: Variant 19-12663723-G-A is Benign according to our data. Variant chr19-12663723-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197684.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}. Variant chr19-12663723-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00234 (356/152292) while in subpopulation NFE AF= 0.00406 (276/67998). AF 95% confidence interval is 0.00367. There are 1 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.743C>T	p.Pro248Leu	missense_variant	5/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.743C>T	p.Pro248Leu	missense_variant	5/24
MAN2B1	XM_005259913.3	c.743C>T	p.Pro248Leu	missense_variant	5/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.743C>T	p.Pro248Leu	missense_variant	5/24	1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.743C>T	p.Pro248Leu	missense_variant	5/24	1		P4
MAN2B1	ENST00000486847.2	c.446C>T	p.Pro149Leu	missense_variant	3/4	4
MAN2B1	ENST00000466794.5	n.725C>T		non_coding_transcript_exon_variant	5/22	2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00230 AC: 570 AN: 247534 Hom.: 3 AF XY: 0.00241 AC XY: 324 AN XY: 134258

Gnomad AFR exome AF: 0.000693

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00455 AC: 6646 AN: 1460520 Hom.: 27 Cov.: 32 AF XY: 0.00444 AC XY: 3224 AN XY: 726580

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000460

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.00548

Gnomad4 OTH exome AF: 0.00380

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74472

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00284 Hom.: 3

Bravo AF: 0.00257

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00235 AC: 285

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:2 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 27, 2019	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MAN2B1: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 30, 2015

- -

MAN2B1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.1	D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.010	D;D;.
Sift4G	Uncertain	0.013	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.45
MVP		0.94
MPC		1.5
ClinPred		0.023	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs117843968; hg19: chr19-12774537; COSMIC: COSV55475040; COSMIC: COSV55475040;