rs2272697

Variant names:

• chr4-102634835-A-G
• rs2272697
• NM_005908.4:c.2368T>C
• MANBA p.Leu790Leu

Your query was ambiguous. Multiple possible variants found:

• chr4-102634835-A-G
• chr4-102634835-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005908.4(MANBA):​c.2368T>C​(p.Leu790Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,786 control chromosomes in the GnomAD database, including 224,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23406 hom., cov: 32)
  • Exomes 𝑓: 0.52 (201098 hom.)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.00
• Publications: 38 publications found

Genes affected

MANBA (HGNC:6831): (mannosidase beta) This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

MANBA Gene-Disease associations (from GenCC):

• beta-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-102634835-A-G is Benign according to our data. Variant chr4-102634835-A-G is described in ClinVar as Benign. ClinVar VariationId is 95320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005908.4. 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
	MANBA	NM_005908.4	MANE Select	c.2368T>C	p.Leu790Leu	synonymous	Exon 16 of 17	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.2368T>C	p.Leu790Leu	synonymous	Exon 16 of 17	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.2506T>C	p.Leu836Leu	synonymous	Exon 17 of 18	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.2467T>C	p.Leu823Leu	synonymous	Exon 17 of 18	ENSP00000624485.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83484 AN: 151954 Hom.: 23368 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.541 AC: 135905 AN: 251324 AF XY: 0.529

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.529

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.521 AC: 762192 AN: 1461714 Hom.: 201098 Cov.: 60 AF XY: 0.518 AC XY: 376758 AN XY: 727158

African (AFR) AF: 0.634 AC: 21229 AN: 33478

American (AMR) AF: 0.724 AC: 32388 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 12879 AN: 26136

East Asian (EAS) AF: 0.493 AC: 19585 AN: 39700

South Asian (SAS) AF: 0.461 AC: 39744 AN: 86252

European-Finnish (FIN) AF: 0.476 AC: 25435 AN: 53418

Middle Eastern (MID) AF: 0.569 AC: 3266 AN: 5736

European-Non Finnish (NFE) AF: 0.518 AC: 575514 AN: 1111886

Other (OTH) AF: 0.532 AC: 32152 AN: 60386

GnomAD4 genome AF: 0.550 AC: 83569 AN: 152072 Hom.: 23406 Cov.: 32 AF XY: 0.548 AC XY: 40779 AN XY: 74348

African (AFR) AF: 0.631 AC: 26160 AN: 41488

American (AMR) AF: 0.618 AC: 9450 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1762 AN: 3468

East Asian (EAS) AF: 0.517 AC: 2669 AN: 5160

South Asian (SAS) AF: 0.451 AC: 2176 AN: 4828

European-Finnish (FIN) AF: 0.471 AC: 4987 AN: 10580

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.508 AC: 34506 AN: 67944

Other (OTH) AF: 0.549 AC: 1157 AN: 2108

Alfa AF: 0.529 Hom.: 33809

Bravo AF: 0.567

Asia WGS AF: 0.505 AC: 1753 AN: 3478

EpiCase AF: 0.516

EpiControl AF: 0.504

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Beta-D-mannosidosis (3)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.6
DANN	Benign	0.50
PhyloP100		3.0
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2272697;

hg19: chr4-103555992;

COSMIC: COSV56964471;

COSMIC: COSV56964471;