chr19-12648277-G-C

Position:

• chr19-12648277-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000528.4(MAN2B1):​c.2562C>G​(p.Ala854Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,609,698 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: MAN2B1 NM_000528.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.71

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]

ENSG00000269242 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-12648277-G-C is Benign according to our data. Variant chr19-12648277-G-C is described in ClinVar as [Benign]. Clinvar id is 328258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12648277-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.71 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00986 (1502/152288) while in subpopulation AFR AF= 0.0321 (1334/41552). AF 95% confidence interval is 0.0307. There are 26 homozygotes in gnomad4. There are 718 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.2562C>G	p.Ala854Ala	synonymous_variant	21/24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.2559C>G	p.Ala853Ala	synonymous_variant	21/24		NP_001166969.1
MAN2B1	XM_005259913.3	c.2565C>G	p.Ala855Ala	synonymous_variant	21/24		XP_005259970.1
MAN2B1	XM_047438841.1	c.1461C>G	p.Ala487Ala	synonymous_variant	14/17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.2562C>G	p.Ala854Ala	synonymous_variant	21/24	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.8	c.2559C>G	p.Ala853Ala	synonymous_variant	21/24	1		ENSP00000221363.4
ENSG00000269242	ENST00000597692.1	n.120C>G		non_coding_transcript_exon_variant	1/5	2		ENSP00000470240.1
MAN2B1	ENST00000466794.5	n.3152C>G		non_coding_transcript_exon_variant	19/22	2

Frequencies

GnomAD3 genomes AF: 0.00983 AC: 1496 AN: 152170 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00277 AC: 650 AN: 234492 Hom.: 11 AF XY: 0.00205 AC XY: 264 AN XY: 128960

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000862

GnomAD4 exome AF: 0.00111 AC: 1622 AN: 1457410 Hom.: 18 Cov.: 32 AF XY: 0.000993 AC XY: 720 AN XY: 725070

Gnomad4 AFR exome AF: 0.0348

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00986 AC: 1502 AN: 152288 Hom.: 26 Cov.: 32 AF XY: 0.00964 AC XY: 718 AN XY: 74460

Gnomad4 AFR AF: 0.0321

Gnomad4 AMR AF: 0.00764

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.000776 Hom.: 0

Bravo AF: 0.0116

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000594

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 15, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Deficiency of alpha-mannosidase Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.12
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs10410289; hg19: chr19-12759091;