15-75356435-C-T

Variant names:

• chr15-75356435-C-T
• NM_006715.4:c.2752G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006715.4(MAN2C1):​c.2752G>A​(p.Ala918Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAN2C1 NM_006715.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

MAN2C1 (HGNC:6827): (mannosidase alpha class 2C member 1) Predicted to enable alpha-mannosidase activity. Predicted to be involved in oligosaccharide catabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NEIL1 (HGNC:18448): (nei like DNA glycosylase 1) This gene is a member of the Nei endonuclease VIII-like gene family which encodes DNA glycosylases. The encoded enzyme participates in the DNA repair pathway by initiating base excision repair by removing damaged bases, primarily oxidized pyrimidines. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2C1	NM_006715.4	c.2752G>A	p.Ala918Thr	missense_variant	Exon 24 of 26	ENST00000267978.10	NP_006706.2
NEIL1	NM_024608.4	c.*1401C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000355059.9	NP_078884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2C1	ENST00000267978.10	c.2752G>A	p.Ala918Thr	missense_variant	Exon 24 of 26	1	NM_006715.4	ENSP00000267978.4
NEIL1	ENST00000355059.9	c.*1401C>T		3_prime_UTR_variant	Exon 10 of 10	2	NM_024608.4	ENSP00000347170.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2752G>A (p.A918T) alteration is located in exon 24 (coding exon 24) of the MAN2C1 gene. This alteration results from a G to A substitution at nucleotide position 2752, causing the alanine (A) at amino acid position 918 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	0.14
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.7	.;.;M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N;N;.
REVEL	Uncertain	0.54
Sift	Benign	0.064	T;T;D;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.87	.;.;P;.
Vest4		0.67
MutPred		0.74		.;.;Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.93
MPC		0.32
ClinPred		0.89	D
GERP RS		3.8
Varity_R		0.34
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-75648776;