chr19-12658134-T-C

Variant names:

• chr19-12658134-T-C
• rs35836657
• NM_000528.4:c.1238A>G

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.1238A>G​(p.Asn413Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,340 control chromosomes in the GnomAD database, including 10,669 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. N413N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.086 (850 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9819 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.04
• Publications: 25 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: ClinGen, Genomics England PanelApp, G2P, Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019977689).
• BP6: Variant 19-12658134-T-C is Benign according to our data. Variant chr19-12658134-T-C is described in ClinVar as Benign. ClinVar VariationId is 129584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 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.1238A>G	p.Asn413Ser	missense	Exon 10 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.1241A>G	p.Asn414Ser	missense	Exon 10 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.1235A>G	p.Asn412Ser	missense	Exon 10 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.1238A>G	p.Asn413Ser	missense	Exon 10 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.1235A>G	p.Asn412Ser	missense	Exon 10 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.1241A>G	p.Asn414Ser	missense	Exon 10 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 13147 AN: 151994 Hom.: 850 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0804

GnomAD2 exomes AF: 0.0901 AC: 22434 AN: 249038 AF XY: 0.0897

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.108 AC: 157991 AN: 1461228 Hom.: 9819 Cov.: 34 AF XY: 0.106 AC XY: 77266 AN XY: 726892

African (AFR) AF: 0.0167 AC: 560 AN: 33478

American (AMR) AF: 0.0460 AC: 2056 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3237 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0229 AC: 1973 AN: 86256

European-Finnish (FIN) AF: 0.196 AC: 10384 AN: 52870

Middle Eastern (MID) AF: 0.0497 AC: 286 AN: 5756

European-Non Finnish (NFE) AF: 0.120 AC: 133578 AN: 1111928

Other (OTH) AF: 0.0979 AC: 5914 AN: 60382

GnomAD4 genome AF: 0.0864 AC: 13149 AN: 152112 Hom.: 850 Cov.: 32 AF XY: 0.0875 AC XY: 6502 AN XY: 74336

African (AFR) AF: 0.0211 AC: 875 AN: 41524

American (AMR) AF: 0.0569 AC: 870 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5164

South Asian (SAS) AF: 0.0214 AC: 103 AN: 4820

European-Finnish (FIN) AF: 0.205 AC: 2169 AN: 10578

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8319 AN: 67942

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.101 Hom.: 1583

Bravo AF: 0.0743

TwinsUK AF: 0.119 AC: 441

ALSPAC AF: 0.115 AC: 443

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.120 AC: 1034

ExAC AF: 0.0897 AC: 10892

Asia WGS AF: 0.0150 AC: 54 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.112

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Deficiency of alpha-mannosidase (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.20
Sift	Benign	0.044	D
Sift4G	Uncertain	0.028	D
Polyphen		0.0050	B
Vest4		0.11
MPC		0.48
ClinPred		0.012	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.51
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35836657; hg19: chr19-12768948; COSMIC: COSV55473709; COSMIC: COSV55473709;