Genetic Variant ENSG00000269242:n.*42G>T (chr19-12646578-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000597692.1(ENSG00000269242):n.*42G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

ENSG00000269242
ENST00000597692.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.08

Publications

0 publications found

Variant links:

Genes affected

ENSG00000269242 (HGNC:):

ENSG00000269242 links:

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, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

MAN2B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.*42G>T	3_prime_UTR_variant	Exon 24 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.*42G>T	3_prime_UTR_variant	Exon 24 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.*42G>T	3_prime_UTR_variant	Exon 24 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_047438841.1 link	c.*42G>T	3_prime_UTR_variant	Exon 17 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000269242	ENST00000597692.1 link	n.*42G>T	non_coding_transcript_exon_variant	Exon 4 of 5	2		ENSP00000470240.1	M0QZ24
MAN2B1	ENST00000456935.7 link	c.*42G>T	3_prime_UTR_variant	Exon 24 of 24	1	NM_000528.4	ENSP00000395473.2	O00754-1
ENSG00000269242	ENST00000597692.1 link	n.*42G>T	3_prime_UTR_variant	Exon 4 of 5	2		ENSP00000470240.1	M0QZ24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.64e-7

AC:

AN:

1308458

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

658826

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30224

American (AMR)

AF:

0.00

AC:

AN:

44346

Ashkenazi Jewish (ASJ)

AF:

0.0000396

AC:

AN:

25228

East Asian (EAS)

AF:

0.00

AC:

AN:

38936

South Asian (SAS)

AF:

0.00

AC:

AN:

83050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

972450

Other (OTH)

AF:

0.00

AC:

AN:

55428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.091

(source)

DANN

Benign

0.48

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over