19-12663748-G-C

Variant names:

• chr19-12663748-G-C
• NM_000528.4:c.718C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000528.4(MAN2B1):​c.718C>G​(p.Arg240Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4	c.718C>G	p.Arg240Gly	missense_variant	Exon 5 of 24	ENST00000456935.7	NP_000519.2
MAN2B1	NM_001173498.2	c.718C>G	p.Arg240Gly	missense_variant	Exon 5 of 24		NP_001166969.1
MAN2B1	XM_005259913.3	c.718C>G	p.Arg240Gly	missense_variant	Exon 5 of 24		XP_005259970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7	c.718C>G	p.Arg240Gly	missense_variant	Exon 5 of 24	1	NM_000528.4	ENSP00000395473.2
MAN2B1	ENST00000221363.8	c.718C>G	p.Arg240Gly	missense_variant	Exon 5 of 24	1		ENSP00000221363.4
MAN2B1	ENST00000486847.2	c.421C>G	p.Arg141Gly	missense_variant	Exon 3 of 4	4		ENSP00000470174.1
MAN2B1	ENST00000466794.5	n.700C>G		non_coding_transcript_exon_variant	Exon 5 of 22	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.4	D;D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.019	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.77		Loss of MoRF binding (P = 0.023);Loss of MoRF binding (P = 0.023);.;
MVP		0.88
MPC		1.6
ClinPred		0.96	D
GERP RS		0.79
Varity_R		0.66
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 37

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12774562;