rs28639634

Variant names:

• chr19-12649910-C-G
• rs28639634
• NM_000528.4:c.2267+3G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-12649910-C-G
• chr19-12649910-C-A
• chr19-12649910-C-T

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.2267+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,612,434 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (115 hom., cov: 28)
  • Exomes 𝑓: 0.0022 (116 hom.)
• Consequence: MAN2B1 NM_000528.4 splice_region, intron
• Scores: Splicing: ADA: 0.05627
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.199
• Publications: 2 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 (BayesDel_noAF=-0.83).
• BP6: Variant 19-12649910-C-G is Benign according to our data. Variant chr19-12649910-C-G is described in ClinVar as Benign. ClinVar VariationId is 328261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.071 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.2267+3G>C		splice_region intron	N/A	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.2270+3G>C		splice_region intron	N/A	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2264+3G>C		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+3G>C		splice_region intron	N/A	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.2264+3G>C		splice_region intron	N/A	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.2315+3G>C		splice_region intron	N/A	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3182 AN: 151682 Hom.: 116 Cov.: 28

Gnomad AFR AF: 0.0733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00709

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0140

GnomAD2 exomes AF: 0.00570 AC: 1433 AN: 251450 AF XY: 0.00416

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00224 AC: 3277 AN: 1460636 Hom.: 116 Cov.: 33 AF XY: 0.00199 AC XY: 1444 AN XY: 726630

African (AFR) AF: 0.0784 AC: 2619 AN: 33418

American (AMR) AF: 0.00411 AC: 184 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00513 AC: 27 AN: 5264

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1111450

Other (OTH) AF: 0.00423 AC: 255 AN: 60324

GnomAD4 genome AF: 0.0210 AC: 3183 AN: 151798 Hom.: 115 Cov.: 28 AF XY: 0.0201 AC XY: 1492 AN XY: 74204

African (AFR) AF: 0.0732 AC: 3018 AN: 41256

American (AMR) AF: 0.00708 AC: 108 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67946

Other (OTH) AF: 0.0138 AC: 29 AN: 2096

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.0255

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Benign	0.36
PhyloP100		0.20
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.056
dbscSNV1_RF	Benign	0.34
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -4

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: rs28639634;

hg19: chr19-12760724;