4-6576596-G-C

Variant names:

• chr4-6576596-G-C
• rs368885291
• NM_015274.3:c.157G>C

Variant summary

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

The NM_015274.3(MAN2B2):​c.157G>C​(p.Ala53Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: MAN2B2 NM_015274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.21

Genes affected

MAN2B2 (HGNC:29623): (mannosidase alpha class 2B member 2) Predicted to enable alpha-mannosidase activity. Predicted to be involved in mannose metabolic process. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B2	NM_015274.3	c.157G>C	p.Ala53Pro	missense_variant	Exon 2 of 19	ENST00000285599.8	NP_056089.1
MAN2B2	NM_001292038.2	c.157G>C	p.Ala53Pro	missense_variant	Exon 2 of 19		NP_001278967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B2	ENST00000285599.8	c.157G>C	p.Ala53Pro	missense_variant	Exon 2 of 19	1	NM_015274.3	ENSP00000285599.3
MAN2B2	ENST00000504248.5	c.157G>C	p.Ala53Pro	missense_variant	Exon 2 of 19	2		ENSP00000423129.1
MAN2B2	ENST00000505907.1	c.151G>C	p.Ala51Pro	missense_variant	Exon 2 of 17	2		ENSP00000426273.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.035	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.74	P;D
Vest4		0.95
MutPred		0.81		Gain of glycosylation at Y57 (P = 0.0242);Gain of glycosylation at Y57 (P = 0.0242);
MVP		0.86
MPC		0.65
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.94
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368885291; hg19: chr4-6578323;