rs75029862

Variant names:

• chr19-12652193-G-A
• rs75029862
• NM_000528.4:c.2006C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-12652193-G-A
• chr19-12652193-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001440570.1(MAN2B1):​c.2009C>T​(p.Pro670Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,614,086 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P670R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (64 hom.)
• Consequence: MAN2B1 NM_001440570.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 8.87
• Publications: 13 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, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075194538).
• BP6: Variant 19-12652193-G-A is Benign according to our data. Variant chr19-12652193-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0051 (777/152222) while in subpopulation EAS AF = 0.0406 (210/5178). AF 95% confidence interval is 0.0361. There are 21 homozygotes in GnomAd4. There are 432 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440570.1. 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.2006C>T	p.Pro669Leu	missense	Exon 16 of 24	NP_000519.2
	MAN2B1	NM_001440570.1		c.2009C>T	p.Pro670Leu	missense	Exon 16 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2003C>T	p.Pro668Leu	missense	Exon 16 of 24	NP_001166969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.2006C>T	p.Pro669Leu	missense	Exon 16 of 24	ENSP00000395473.2
	MAN2B1	ENST00000221363.9	TSL:1	c.2003C>T	p.Pro668Leu	missense	Exon 16 of 24	ENSP00000221363.4
	MAN2B1	ENST00000964003.1		c.2054C>T	p.Pro685Leu	missense	Exon 16 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 779 AN: 152104 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0410

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00924 AC: 2324 AN: 251466 AF XY: 0.00791

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0408

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0431

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00259 AC: 3784 AN: 1461864 Hom.: 64 Cov.: 32 AF XY: 0.00243 AC XY: 1770 AN XY: 727240

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0407 AC: 1821 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.0367 AC: 1455 AN: 39698

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86248

European-Finnish (FIN) AF: 0.000805 AC: 43 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000124 AC: 138 AN: 1111996

Other (OTH) AF: 0.00344 AC: 208 AN: 60394

GnomAD4 genome AF: 0.00510 AC: 777 AN: 152222 Hom.: 21 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74430

African (AFR) AF: 0.000698 AC: 29 AN: 41532

American (AMR) AF: 0.0318 AC: 485 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.0406 AC: 210 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68014

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00259 Hom.: 14

Bravo AF: 0.00775

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00767 AC: 931

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		8.9
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.59
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.68
MVP		0.89
MPC		0.58
ClinPred		0.032	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.68
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75029862; hg19: chr19-12763007; COSMIC: COSV55475514; COSMIC: COSV55475514;