chr4-6575322-G-A

Variant names:

• chr4-6575322-G-A
• rs200406024
• NM_015274.3:c.112G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_015274.3(MAN2B2):​c.112G>A​(p.Asp38Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000232 in 1,584,442 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: MAN2B2 NM_015274.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.97

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_benign. Variant got -2 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity MA2B2_HUMAN
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B2	NM_015274.3	c.112G>A	p.Asp38Asn	missense_variant	Exon 1 of 19	ENST00000285599.8	NP_056089.1
MAN2B2	NM_001292038.2	c.112G>A	p.Asp38Asn	missense_variant	Exon 1 of 19		NP_001278967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B2	ENST00000285599.8	c.112G>A	p.Asp38Asn	missense_variant	Exon 1 of 19	1	NM_015274.3	ENSP00000285599.3
MAN2B2	ENST00000504248.5	c.112G>A	p.Asp38Asn	missense_variant	Exon 1 of 19	2		ENSP00000423129.1
MAN2B2	ENST00000505907.1	c.106G>A	p.Asp36Asn	missense_variant	Exon 1 of 17	2		ENSP00000426273.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000291 AC: 58 AN: 199310 Hom.: 0 AF XY: 0.000319 AC XY: 35 AN XY: 109630

Gnomad AFR exome AF: 0.0000848

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000453

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000358

Gnomad OTH exome AF: 0.000396

GnomAD4 exome AF: 0.000238 AC: 341 AN: 1432078 Hom.: 2 Cov.: 31 AF XY: 0.000239 AC XY: 170 AN XY: 710966

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000496

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.000353

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74506

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000433 Hom.: 0

Bravo AF: 0.000159

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000250 AC: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Mar 25, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 24, 2025

Variant summary: MAN2B2 c.112G>A (p.Asp38Asn) results in a conservative amino acid change located in the Glycoside hydrosylase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 199310 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MAN2B2 causing MAN2B2 Deficiency, allowing no conclusion about variant significance. c.112G>A has been reported in the literature in individuals affected with MAN2B2 Deficiency. These report(s) do not provide unequivocal conclusions about association of the variant with MAN2B2 Deficiency. Co-occurrences with other pathogenic variant(s) have been reported (DNM1 c.97C>T, p.Gln33*), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 31775018, 34172529). ClinVar contains an entry for this variant (Variation ID: 1065157). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.83
MVP		0.83
MPC		0.56
ClinPred		0.95	D
GERP RS		1.9
Varity_R		0.94
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs200406024; hg19: chr4-6577049;