15-75356641-C-T

Variant names:

• chr15-75356641-C-T
• rs756198744
• NM_006715.4:c.2702G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006715.4(MAN2C1):​c.2702G>A​(p.Arg901His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,570,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R901C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MAN2C1 NM_006715.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.512
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19564328).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006715.4. 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
	MAN2C1	NM_006715.4	MANE Select	c.2702G>A	p.Arg901His	missense	Exon 23 of 26	NP_006706.2
	NEIL1	NM_024608.4	MANE Select	c.*1607C>T		3_prime_UTR	Exon 10 of 10	NP_078884.2	Q96FI4
	MAN2C1	NM_001256494.2		c.2753G>A	p.Arg918His	missense	Exon 23 of 26	NP_001243423.1	Q9NTJ4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2C1	ENST00000267978.10	TSL:1 MANE Select	c.2702G>A	p.Arg901His	missense	Exon 23 of 26	ENSP00000267978.4	Q9NTJ4-1
	MAN2C1	ENST00000565683.5	TSL:1	c.2753G>A	p.Arg918His	missense	Exon 23 of 26	ENSP00000457788.1	Q9NTJ4-4
	MAN2C1	ENST00000569482.5	TSL:1	c.2702G>A	p.Arg901His	missense	Exon 23 of 26	ENSP00000455998.1	Q9NTJ4-2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000163 AC: 3 AN: 183572 AF XY: 0.0000203

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000391

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000310 AC: 44 AN: 1418566 Hom.: 0 Cov.: 33 AF XY: 0.0000256 AC XY: 18 AN XY: 701934

African (AFR) AF: 0.00 AC: 0 AN: 32496

American (AMR) AF: 0.00 AC: 0 AN: 37504

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25422

East Asian (EAS) AF: 0.000214 AC: 8 AN: 37398

South Asian (SAS) AF: 0.00 AC: 0 AN: 81742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4666

European-Non Finnish (NFE) AF: 0.0000147 AC: 16 AN: 1090458

Other (OTH) AF: 0.000324 AC: 19 AN: 58726

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000251 AC: 3

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital disorder of deglycosylation 2 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.21	N
PhyloP100		0.51
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.13
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.27
MutPred		0.58		Loss of phosphorylation at T899 (P = 0.1268)
MVP		0.52
MPC		0.097
ClinPred		0.17	T
GERP RS		2.9
Varity_R		0.042
gMVP		0.21
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs756198744; hg19: chr15-75648982; COSMIC: COSV99145207; COSMIC: COSV99145207;