rs547349667

Variant names:

• chr19-12646515-G-C
• rs547349667
• NM_000528.4:c.*105C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-12646515-G-C
• chr19-12646515-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000528.4(MAN2B1):​c.*105C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 871,058 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: MAN2B1 NM_000528.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.788
• 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)

ENSG00000269242 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS2: High Homozygotes in GnomAdExome4 at 4 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.*105C>G		3_prime_UTR	Exon 24 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.*105C>G		3_prime_UTR	Exon 24 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.*105C>G		3_prime_UTR	Exon 24 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.*105C>G		3_prime_UTR	Exon 24 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.*105C>G		3_prime_UTR	Exon 24 of 24	ENSP00000221363.4	O00754-2
	ENSG00000269242	ENST00000597692.1	TSL:2	n.*105C>G		non_coding_transcript_exon	Exon 4 of 5	ENSP00000470240.1	M0QZ24

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00104 AC: 747 AN: 718800 Hom.: 4 Cov.: 9 AF XY: 0.00101 AC XY: 384 AN XY: 380434

African (AFR) AF: 0.000105 AC: 2 AN: 19022

American (AMR) AF: 0.000136 AC: 5 AN: 36642

Ashkenazi Jewish (ASJ) AF: 0.000143 AC: 3 AN: 20950

East Asian (EAS) AF: 0.00 AC: 0 AN: 34738

South Asian (SAS) AF: 0.00103 AC: 70 AN: 68266

European-Finnish (FIN) AF: 0.00478 AC: 239 AN: 50046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4358

European-Non Finnish (NFE) AF: 0.000889 AC: 399 AN: 448878

Other (OTH) AF: 0.000808 AC: 29 AN: 35900

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000967 AC XY: 72 AN XY: 74462

African (AFR) AF: 0.000120 AC: 5 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.000506

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of alpha-mannosidase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.0
DANN	Benign	0.58
PhyloP100		-0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs547349667; hg19: chr19-12757329;