19-12649904-ACC-ACCC

Position:

• chr19-12649904-ACC-ACCC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000528.4(MAN2B1):​c.2267+8_2267+9insG variant causes a 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. 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.840

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 290029.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
• 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 male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.2267+8_2267+9insG		intron_variant		ENST00000456935.7
MAN2B1	NM_001173498.2	c.2264+8_2264+9insG		intron_variant
MAN2B1	XM_005259913.3	c.2270+8_2270+9insG		intron_variant
MAN2B1	XM_047438841.1	c.1166+8_1166+9insG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2267+8_2267+9insG		intron_variant		1	NM_000528.4	A1
MAN2B1	ENST00000221363.8	c.2264+8_2264+9insG		intron_variant		1		P4
MAN2B1	ENST00000466794.5	n.2857+8_2857+9insG		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.00414 AC: 1040 AN: 251360 Hom.: 6 AF XY: 0.00423 AC XY: 575 AN XY: 135838

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 SAS exome AF: 0.00163

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

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.000944

Gnomad4 EAS exome AF: 0.0000263

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00801

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

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00332

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000405

Gnomad4 SAS AF: 0.000471

Gnomad4 FIN AF: 0.000837

Gnomad4 NFE AF: 0.00917

Gnomad4 OTH AF: 0.00673

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00824

EpiControl AF: 0.00901

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of alpha-mannosidase Uncertain:1 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MAN2B1: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs572289342; hg19: chr19-12760718;