19-12655780-G-C

Position:

• chr19-12655780-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000528.4(MAN2B1):​c.1744C>G​(p.Gln582Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,610,168 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (14 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.542

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038622022).
• BP6: Variant 19-12655780-G-C is Benign according to our data. Variant chr19-12655780-G-C is described in ClinVar as [Benign]. Clinvar id is 457139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12655780-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00722 (1099/152236) while in subpopulation AFR AF= 0.0255 (1060/41548). AF 95% confidence interval is 0.0242. There are 15 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN2B1	NM_000528.4	c.1744C>G	p.Gln582Glu	missense_variant	14/24	ENST00000456935.7
MAN2B1	NM_001173498.2	c.1741C>G	p.Gln581Glu	missense_variant	14/24
MAN2B1	XM_005259913.3	c.1747C>G	p.Gln583Glu	missense_variant	14/24
MAN2B1	XM_047438841.1	c.643C>G	p.Gln215Glu	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN2B1	ENST00000456935.7	c.1744C>G	p.Gln582Glu	missense_variant	14/24	1	NM_000528.4	A1

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1097 AN: 152118 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00180 AC: 450 AN: 250378 Hom.: 6 AF XY: 0.00129 AC XY: 175 AN XY: 135358

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000750 AC: 1094 AN: 1457932 Hom.: 14 Cov.: 31 AF XY: 0.000635 AC XY: 460 AN XY: 724414

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.000964

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00722 AC: 1099 AN: 152236 Hom.: 15 Cov.: 31 AF XY: 0.00670 AC XY: 499 AN XY: 74444

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000871 Hom.: 2

Bravo AF: 0.00821

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of alpha-mannosidase Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Fulgent Genetics, Fulgent Genetics	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.94
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.078
Sift	Benign	0.14	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.046	B;.
Vest4		0.082
MVP		0.66
MPC		0.26
ClinPred		0.00064	T
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59357922; hg19: chr19-12766594;