rs1054486

Variant names:

• chr19-12663394-G-C
• rs1054486
• NM_000528.4:c.832C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-12663394-G-C
• chr19-12663394-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000528.4(MAN2B1):​c.832C>G​(p.Leu278Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,613,786 control chromosomes in the GnomAD database, including 65,081 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L278M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (7350 hom., cov: 31)
  • Exomes 𝑓: 0.27 (57731 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.440
• Publications: 38 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.7047944E-4).
• BP6: Variant 19-12663394-G-C is Benign according to our data. Variant chr19-12663394-G-C is described in ClinVar as Benign. ClinVar VariationId is 93217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

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.832C>G	p.Leu278Val	missense	Exon 6 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.832C>G	p.Leu278Val	missense	Exon 6 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.832C>G	p.Leu278Val	missense	Exon 6 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.832C>G	p.Leu278Val	missense	Exon 6 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.832C>G	p.Leu278Val	missense	Exon 6 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.832C>G	p.Leu278Val	missense	Exon 6 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45332 AN: 151826 Hom.: 7348 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.251 AC: 62983 AN: 251424 AF XY: 0.252

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.295

Gnomad EAS exome AF: 0.0307

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.274 AC: 400759 AN: 1461842 Hom.: 57731 Cov.: 39 AF XY: 0.272 AC XY: 198100 AN XY: 727230

African (AFR) AF: 0.388 AC: 12981 AN: 33480

American (AMR) AF: 0.157 AC: 7033 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7792 AN: 26134

East Asian (EAS) AF: 0.0301 AC: 1194 AN: 39700

South Asian (SAS) AF: 0.180 AC: 15545 AN: 86258

European-Finnish (FIN) AF: 0.344 AC: 18386 AN: 53406

Middle Eastern (MID) AF: 0.322 AC: 1857 AN: 5768

European-Non Finnish (NFE) AF: 0.287 AC: 319635 AN: 1111980

Other (OTH) AF: 0.270 AC: 16336 AN: 60394

GnomAD4 genome AF: 0.299 AC: 45360 AN: 151944 Hom.: 7350 Cov.: 31 AF XY: 0.295 AC XY: 21932 AN XY: 74248

African (AFR) AF: 0.383 AC: 15853 AN: 41400

American (AMR) AF: 0.192 AC: 2930 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3466

East Asian (EAS) AF: 0.0305 AC: 158 AN: 5180

South Asian (SAS) AF: 0.172 AC: 829 AN: 4824

European-Finnish (FIN) AF: 0.353 AC: 3714 AN: 10536

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20041 AN: 67972

Other (OTH) AF: 0.264 AC: 559 AN: 2114

Alfa AF: 0.284 Hom.: 4846

Bravo AF: 0.291

TwinsUK AF: 0.287 AC: 1063

ALSPAC AF: 0.289 AC: 1114

ESP6500AA AF: 0.376 AC: 1655

ESP6500EA AF: 0.289 AC: 2488

ExAC AF: 0.257 AC: 31144

Asia WGS AF: 0.120 AC: 417 AN: 3478

EpiCase AF: 0.291

EpiControl AF: 0.293

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Deficiency of alpha-mannosidase (5)
-	-	5	not specified (5)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.010
DANN	Benign	0.46
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.00077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.72	N
PhyloP100		-0.44
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.10
Sift	Benign	0.58	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.56
ClinPred		0.0051	T
GERP RS		-7.4
Varity_R		0.036
gMVP		0.49
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1054486; hg19: chr19-12774208; COSMIC: COSV55471017; COSMIC: COSV55471017;