rs117843968

Variant names:

• chr19-12663723-G-A
• rs117843968
• NM_000528.4:c.743C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-12663723-G-A
• chr19-12663723-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000528.4(MAN2B1):​c.743C>T​(p.Pro248Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,612,812 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P248R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (27 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.35
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03565052).
• BP6: Variant 19-12663723-G-A is Benign according to our data. Variant chr19-12663723-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197684.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00234 (356/152292) while in subpopulation NFE AF = 0.00406 (276/67998). AF 95% confidence interval is 0.00367. There are 1 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 AR gene

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.743C>T	p.Pro248Leu	missense	Exon 5 of 24	NP_000519.2	O00754-1
	MAN2B1	NM_001440570.1		c.743C>T	p.Pro248Leu	missense	Exon 5 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.743C>T	p.Pro248Leu	missense	Exon 5 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.743C>T	p.Pro248Leu	missense	Exon 5 of 24	ENSP00000395473.2	O00754-1
	MAN2B1	ENST00000221363.9	TSL:1	c.743C>T	p.Pro248Leu	missense	Exon 5 of 24	ENSP00000221363.4	O00754-2
	MAN2B1	ENST00000964003.1		c.743C>T	p.Pro248Leu	missense	Exon 5 of 24	ENSP00000634062.1

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00230 AC: 570 AN: 247534 AF XY: 0.00241

Gnomad AFR exome AF: 0.000693

Gnomad AMR exome AF: 0.00152

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00455 AC: 6646 AN: 1460520 Hom.: 27 Cov.: 32 AF XY: 0.00444 AC XY: 3224 AN XY: 726580

African (AFR) AF: 0.000687 AC: 23 AN: 33456

American (AMR) AF: 0.00132 AC: 59 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00186 AC: 160 AN: 86168

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 53008

Middle Eastern (MID) AF: 0.00124 AC: 7 AN: 5650

European-Non Finnish (NFE) AF: 0.00548 AC: 6094 AN: 1111590

Other (OTH) AF: 0.00380 AC: 229 AN: 60332

GnomAD4 genome AF: 0.00234 AC: 356 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00216 AC XY: 161 AN XY: 74472

African (AFR) AF: 0.000794 AC: 33 AN: 41564

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 67998

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00317 Hom.: 7

Bravo AF: 0.00257

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00235 AC: 285

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Deficiency of alpha-mannosidase (5)
-	-	3	not provided (3)
-	-	1	MAN2B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.036	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.45
MVP		0.94
MPC		1.5
ClinPred		0.023	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.72
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs117843968; hg19: chr19-12774537; COSMIC: COSV55475040; COSMIC: COSV55475040;