Genetic Variant TPCN2:p.Glu9Asp (chr11-69049024-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_139075.4(TPCN2):c.27G>C(p.Glu9Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,240,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 9.2e-7 ( 0 hom. )

Consequence

TPCN2
NM_139075.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.221

Publications

1 publications found

Variant links:

Genes affected

TPCN2 (HGNC:20820): (two pore segment channel 2) This gene encodes a putative cation-selective ion channel with two repeats of a six-transmembrane-domain. The protein localizes to lysosomal membranes and enables nicotinic acid adenine dinucleotide phosphate (NAADP) -induced calcium ion release from lysosome-related stores. This ubiquitously expressed gene has elevated expression in liver and kidney. Two common nonsynonymous SNPs in this gene strongly associate with blond versus brown hair pigmentation.[provided by RefSeq, Dec 2009]

TPCN2 Gene-Disease associations (from GenCC):

albinism
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TPCN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09563133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4 link	c.27G>C	p.Glu9Asp	missense_variant	Exon 1 of 25	ENST00000294309.8	NP_620714.2	Q8NHX9Q59G56

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8 link	c.27G>C	p.Glu9Asp	missense_variant	Exon 1 of 25	1	NM_139075.4	ENSP00000294309.3		Q8NHX9

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.19e-7

AC:

AN:

1088560

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

514342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23004

American (AMR)

AF:

0.00

AC:

AN:

8416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14368

East Asian (EAS)

AF:

0.00

AC:

AN:

26524

South Asian (SAS)

AF:

0.00

AC:

AN:

19730

European-Finnish (FIN)

AF:

0.0000350

AC:

AN:

28552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3906

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920272

Other (OTH)

AF:

0.00

AC:

AN:

43788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.71

T;.;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.096

T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Benign

1.9

L;.;.;.

PhyloP100

-0.22

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.42

N;.;N;.

REVEL

Benign

0.23

Sift

Benign

0.055

T;.;D;.

Sift4G

Benign

0.24

T;.;T;.

Polyphen

0.0020

B;.;B;.

Vest4

0.059

MutPred

0.047

Loss of glycosylation at S8 (P = 0.1232);Loss of glycosylation at S8 (P = 0.1232);Loss of glycosylation at S8 (P = 0.1232);Loss of glycosylation at S8 (P = 0.1232);

MVP

0.45

MPC

0.67

ClinPred

0.14

GERP RS

-2.3

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.081

gMVP

0.17

Mutation Taster

=92/8

polymorphism

(source)

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

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chr11-69049024-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over