4-6578421-T-C

Variant names:

• chr4-6578421-T-C
• rs1726152734
• NM_015274.3:c.314T>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.314T>C​(p.Leu105Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAN2B2 NM_015274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.44

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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B2	NM_015274.3	c.314T>C	p.Leu105Pro	missense_variant	Exon 3 of 19	ENST00000285599.8	NP_056089.1
MAN2B2	NM_001292038.2	c.314T>C	p.Leu105Pro	missense_variant	Exon 3 of 19		NP_001278967.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B2	ENST00000285599.8	c.314T>C	p.Leu105Pro	missense_variant	Exon 3 of 19	1	NM_015274.3	ENSP00000285599.3
MAN2B2	ENST00000504248.5	c.314T>C	p.Leu105Pro	missense_variant	Exon 3 of 19	2		ENSP00000423129.1
MAN2B2	ENST00000505907.1	c.308T>C	p.Leu103Pro	missense_variant	Exon 3 of 17	2		ENSP00000426273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461364 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314T>C (p.L105P) alteration is located in exon 3 (coding exon 3) of the MAN2B2 gene. This alteration results from a T to C substitution at nucleotide position 314, causing the leucine (L) at amino acid position 105 to be replaced by a proline (P). 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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.90		Gain of disorder (P = 0.0304);Gain of disorder (P = 0.0304);
MVP		0.87
MPC		0.71
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.96

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: rs1726152734; hg19: chr4-6580148;