chr4-6576599-G-C

Variant names:

• chr4-6576599-G-C
• rs145563570
• NM_015274.3:c.160G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015274.3(MAN2B2):​c.160G>C​(p.Ala54Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,613,204 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00043 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (8 hom.)
• Consequence: MAN2B2 NM_015274.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.85
• Publications: 3 publications found

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]

MAN2B2 Gene-Disease associations (from GenCC):

• MAN2B2 deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014566481).
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015274.3. 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
	MAN2B2	NM_015274.3	MANE Select	c.160G>C	p.Ala54Pro	missense	Exon 2 of 19	NP_056089.1	Q9Y2E5-1
	MAN2B2	NM_001292038.2		c.160G>C	p.Ala54Pro	missense	Exon 2 of 19	NP_001278967.1	E9PCD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B2	ENST00000285599.8	TSL:1 MANE Select	c.160G>C	p.Ala54Pro	missense	Exon 2 of 19	ENSP00000285599.3	Q9Y2E5-1
	MAN2B2	ENST00000868575.1		c.160G>C	p.Ala54Pro	missense	Exon 2 of 20	ENSP00000538634.1
	MAN2B2	ENST00000868574.1		c.298G>C	p.Ala100Pro	missense	Exon 3 of 20	ENSP00000538633.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152216 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000868 AC: 218 AN: 251060 AF XY: 0.000839

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000479 AC: 700 AN: 1460988 Hom.: 8 Cov.: 31 AF XY: 0.000472 AC XY: 343 AN XY: 726808

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 469 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52918

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111732

Other (OTH) AF: 0.00149 AC: 90 AN: 60368

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152216 Hom.: 1 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74356

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000446 Hom.: 0

Bravo AF: 0.000544

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.18
Sift	Benign	0.080	T
Sift4G	Benign	0.066	T
Polyphen		0.50	P
Vest4		0.67
MutPred		0.67		Gain of glycosylation at Y57 (P = 0.0242)
MVP		0.29
MPC		0.35
ClinPred		0.094	T
GERP RS		3.0
Varity_R		0.85
gMVP		0.74
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs145563570; hg19: chr4-6578326;