rs34544747

Variant names:

• chr19-12657035-C-A
• rs34544747
• NM_000528.4:c.1441G>T
• MAN2B1 p.Ala481Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000528.4(MAN2B1):​c.1441G>T​(p.Ala481Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,611,712 control chromosomes in the GnomAD database, including 1,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A481A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.067 (880 hom., cov: 32)
  • Exomes 𝑓: 0.019 (976 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.73
• Publications: 15 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: Myriad Women's Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021640658).
• BP6: Variant 19-12657035-C-A is Benign according to our data. Variant chr19-12657035-C-A is described in ClinVar as Benign. ClinVar VariationId is 93210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000528.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	NM_000528.4	MANE Select	c.1441G>T	p.Ala481Ser	missense	Exon 12 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.1444G>T	p.Ala482Ser	missense	Exon 12 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.1438G>T	p.Ala480Ser	missense	Exon 12 of 24	NP_001166969.1	O00754-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.1441G>T	p.Ala481Ser	missense	Exon 12 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.1438G>T	p.Ala480Ser	missense	Exon 12 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.1444G>T	p.Ala482Ser	missense	Exon 12 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.0671 AC: 10209 AN: 152148 Hom.: 878 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0680

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0650

GnomAD2 exomes AF: 0.0262 AC: 6482 AN: 247852 AF XY: 0.0225

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0644

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0193 AC: 28198 AN: 1459446 Hom.: 976 Cov.: 31 AF XY: 0.0185 AC XY: 13467 AN XY: 726046

African (AFR) AF: 0.204 AC: 6804 AN: 33422

American (AMR) AF: 0.0227 AC: 1012 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1698 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00452 AC: 389 AN: 86084

European-Finnish (FIN) AF: 0.00115 AC: 60 AN: 52058

Middle Eastern (MID) AF: 0.0451 AC: 260 AN: 5764

European-Non Finnish (NFE) AF: 0.0145 AC: 16166 AN: 1111338

Other (OTH) AF: 0.0299 AC: 1807 AN: 60348

GnomAD4 genome AF: 0.0672 AC: 10229 AN: 152266 Hom.: 880 Cov.: 32 AF XY: 0.0648 AC XY: 4825 AN XY: 74448

African (AFR) AF: 0.197 AC: 8173 AN: 41524

American (AMR) AF: 0.0391 AC: 599 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0680 AC: 236 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00641 AC: 31 AN: 4834

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10632

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0145 AC: 985 AN: 68016

Other (OTH) AF: 0.0643 AC: 136 AN: 2114

Alfa AF: 0.0301 Hom.: 958

Bravo AF: 0.0766

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0175

EpiControl AF: 0.0184

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Deficiency of alpha-mannosidase (4)
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.23
Sift	Benign	0.59	T
Sift4G	Benign	0.63	T
Varity_R		0.076
gMVP		0.53
Mutation Taster		=97/3	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34544747;

hg19: chr19-12767849;

COSMIC: COSV55471993;

COSMIC: COSV55471993;