chr4-6576599-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015274.3(MAN2B2):​c.160G>A​(p.Ala54Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,613,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: MAN2B2 NM_015274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15282774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B2	NM_015274.3	c.160G>A	p.Ala54Thr	missense_variant	Exon 2 of 19	ENST00000285599.8	NP_056089.1
MAN2B2	NM_001292038.2	c.160G>A	p.Ala54Thr	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.160G>A	p.Ala54Thr	missense_variant	Exon 2 of 19	1	NM_015274.3	ENSP00000285599.3
MAN2B2	ENST00000504248.5	c.160G>A	p.Ala54Thr	missense_variant	Exon 2 of 19	2		ENSP00000423129.1
MAN2B2	ENST00000505907.1	c.154G>A	p.Ala52Thr	missense_variant	Exon 2 of 17	2		ENSP00000426273.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251060 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135842

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000363 AC: 530 AN: 1460988 Hom.: 0 Cov.: 31 AF XY: 0.000384 AC XY: 279 AN XY: 726808

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74356

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.160G>A (p.A54T) alteration is located in exon 2 (coding exon 2) of the MAN2B2 gene. This alteration results from a G to A substitution at nucleotide position 160, causing the alanine (A) at amino acid position 54 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.54	N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.060
Sift	Benign	0.13	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.64	P;P
Vest4		0.44
MVP		0.19
MPC		0.20
ClinPred		0.085	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.15
gMVP		0.23

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: rs145563570; hg19: chr4-6578326; COSMIC: COSV53456854;