rs1054487

Variant names:

• chr19-12661351-G-A
• rs1054487
• NM_000528.4:c.935C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-12661351-G-A
• chr19-12661351-G-T
• chr19-12661351-G-C

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.935C>T​(p.Thr312Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,610,788 control chromosomes in the GnomAD database, including 121,803 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T312N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13848 hom., cov: 32)
  • Exomes 𝑓: 0.37 (107955 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.96
• Publications: 49 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=1.6364455E-4).
• BP6: Variant 19-12661351-G-A is Benign according to our data. Variant chr19-12661351-G-A is described in ClinVar as Benign. ClinVar VariationId is 93218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 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.935C>T	p.Thr312Ile	missense	Exon 7 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.935C>T	p.Thr312Ile	missense	Exon 7 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.935C>T	p.Thr312Ile	missense	Exon 7 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.935C>T	p.Thr312Ile	missense	Exon 7 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.935C>T	p.Thr312Ile	missense	Exon 7 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.935C>T	p.Thr312Ile	missense	Exon 7 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62314 AN: 151958 Hom.: 13826 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.519

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.418

GnomAD2 exomes AF: 0.332 AC: 83511 AN: 251472 AF XY: 0.333

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.0505

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.373 AC: 544784 AN: 1458712 Hom.: 107955 Cov.: 33 AF XY: 0.371 AC XY: 269149 AN XY: 725794

African (AFR) AF: 0.557 AC: 18626 AN: 33412

American (AMR) AF: 0.218 AC: 9758 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 13594 AN: 26100

East Asian (EAS) AF: 0.0497 AC: 1971 AN: 39684

South Asian (SAS) AF: 0.236 AC: 20357 AN: 86216

European-Finnish (FIN) AF: 0.298 AC: 15902 AN: 53384

Middle Eastern (MID) AF: 0.465 AC: 2673 AN: 5750

European-Non Finnish (NFE) AF: 0.396 AC: 439558 AN: 1109174

Other (OTH) AF: 0.371 AC: 22345 AN: 60280

GnomAD4 genome AF: 0.410 AC: 62360 AN: 152076 Hom.: 13848 Cov.: 32 AF XY: 0.400 AC XY: 29725 AN XY: 74340

African (AFR) AF: 0.549 AC: 22782 AN: 41474

American (AMR) AF: 0.293 AC: 4473 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1803 AN: 3472

East Asian (EAS) AF: 0.0544 AC: 281 AN: 5168

South Asian (SAS) AF: 0.227 AC: 1095 AN: 4830

European-Finnish (FIN) AF: 0.298 AC: 3147 AN: 10566

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27495 AN: 67970

Other (OTH) AF: 0.415 AC: 874 AN: 2108

Alfa AF: 0.400 Hom.: 38013

Bravo AF: 0.418

TwinsUK AF: 0.392 AC: 1454

ALSPAC AF: 0.396 AC: 1527

ESP6500AA AF: 0.537 AC: 2366

ESP6500EA AF: 0.411 AC: 3533

ExAC AF: 0.340 AC: 41261

EpiCase AF: 0.418

EpiControl AF: 0.409

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Deficiency of alpha-mannosidase (5)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.35
DANN	Benign	0.13
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00016	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.8	N
PhyloP100		2.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.072
MPC		0.61
ClinPred		0.0065	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.35
Mutation Taster		=99/1	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: rs1054487; hg19: chr19-12772165; COSMIC: COSV55471011; COSMIC: COSV55471011;