19-12649904-ACC-AC

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000528.4(MAN2B1):​c.2267+8delG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,535,298 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000075 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-12649904-AC-A is Benign according to our data. Variant chr19-12649904-AC-A is described in ClinVar as Benign. ClinVar VariationId is 2996167.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2267+8delG		splice_region_variant, intron_variant	Intron 18 of 23	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001440570.1	c.2270+8delG		splice_region_variant, intron_variant	Intron 18 of 23		NP_001427499.1
MAN2B1	NM_001173498.2	c.2264+8delG		splice_region_variant, intron_variant	Intron 18 of 23		NP_001166969.1
MAN2B1	XM_047438841.1	c.1166+8delG		splice_region_variant, intron_variant	Intron 11 of 16		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2267+8delG		splice_region_variant, intron_variant	Intron 18 of 23	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.9	c.2264+8delG		splice_region_variant, intron_variant	Intron 18 of 23	1		ENSP00000221363.4
MAN2B1	ENST00000466794.5	n.2857+8delG		splice_region_variant, intron_variant	Intron 16 of 21	2

Frequencies

GnomAD3 genomes AF: 0.00000747 AC: 1 AN: 133872 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1401426 Hom.: 0 Cov.: 33 AF XY: 0.00000286 AC XY: 2 AN XY: 698456

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32094

American (AMR) AF: 0.00 AC: 0 AN: 43888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24354

East Asian (EAS) AF: 0.00 AC: 0 AN: 38070

South Asian (SAS) AF: 0.00 AC: 0 AN: 85686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4860

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1066138

Other (OTH) AF: 0.0000175 AC: 1 AN: 57270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000747 AC: 1 AN: 133872 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 64792

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 34886

American (AMR) AF: 0.00 AC: 0 AN: 13252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4944

South Asian (SAS) AF: 0.00 AC: 0 AN: 4268

European-Finnish (FIN) AF: 0.000120 AC: 1 AN: 8366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62090

Other (OTH) AF: 0.00 AC: 0 AN: 1762

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of alpha-mannosidase Benign:1

Feb 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;