19-12649904-ACC-ACCC

Variant names:

• chr19-12649904-A-AC
• rs572289342
• NM_000528.4:c.2267+8dupG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000528.4(MAN2B1):​c.2267+8dupG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 1,535,290 control chromosomes in the GnomAD database, including 61 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 28)
  • Exomes 𝑓: 0.0083 (58 hom.)
• Consequence: MAN2B1 NM_000528.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.840
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 19-12649904-A-AC is Benign according to our data. Variant chr19-12649904-A-AC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290029.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00524 (702/133926) while in subpopulation NFE AF = 0.00917 (569/62074). AF 95% confidence interval is 0.00854. There are 3 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.2267+8dupG		splice_region intron	N/A	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.2270+8dupG		splice_region intron	N/A	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2264+8dupG		splice_region intron	N/A	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.2267+8_2267+9insG		splice_region intron	N/A	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.2264+8_2264+9insG		splice_region intron	N/A	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.2315+8_2315+9insG		splice_region intron	N/A	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 702 AN: 133860 Hom.: 3 Cov.: 28

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00363

Gnomad AMR AF: 0.00332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000405

Gnomad SAS AF: 0.000469

Gnomad FIN AF: 0.000837

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00917

Gnomad OTH AF: 0.00681

GnomAD2 exomes AF: 0.00414 AC: 1040 AN: 251360 AF XY: 0.00423

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00832 AC: 11658 AN: 1401364 Hom.: 58 Cov.: 33 AF XY: 0.00790 AC XY: 5520 AN XY: 698422

African (AFR) AF: 0.00131 AC: 42 AN: 32096

American (AMR) AF: 0.00248 AC: 109 AN: 43888

Ashkenazi Jewish (ASJ) AF: 0.000944 AC: 23 AN: 24354

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38070

South Asian (SAS) AF: 0.00163 AC: 140 AN: 85688

European-Finnish (FIN) AF: 0.00112 AC: 55 AN: 49066

Middle Eastern (MID) AF: 0.000617 AC: 3 AN: 4860

European-Non Finnish (NFE) AF: 0.0102 AC: 10826 AN: 1066072

Other (OTH) AF: 0.00801 AC: 459 AN: 57270

GnomAD4 genome AF: 0.00524 AC: 702 AN: 133926 Hom.: 3 Cov.: 28 AF XY: 0.00467 AC XY: 303 AN XY: 64872

African (AFR) AF: 0.00180 AC: 63 AN: 34964

American (AMR) AF: 0.00332 AC: 44 AN: 13270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3192

East Asian (EAS) AF: 0.000405 AC: 2 AN: 4934

South Asian (SAS) AF: 0.000471 AC: 2 AN: 4250

European-Finnish (FIN) AF: 0.000837 AC: 7 AN: 8368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00917 AC: 569 AN: 62074

Other (OTH) AF: 0.00673 AC: 12 AN: 1784

Alfa AF: 0.00187 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00824

EpiControl AF: 0.00901

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Deficiency of alpha-mannosidase (3)
-	1	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.84
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs572289342; hg19: chr19-12760718;