dbSNP rs753794712: TPCN2:p.Pro23Arg (chr11-69049065-C-G) – 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.68C>G(p.Pro23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000161 in 1,242,574 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P23L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 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: -0.802

Publications

0 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=0.17569742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4 link	c.68C>G	p.Pro23Arg	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.68C>G	p.Pro23Arg	missense_variant	Exon 1 of 25	1	NM_139075.4	ENSP00000294309.3		Q8NHX9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.17e-7

AC:

AN:

1090400

Hom.:

Cov.:

AF XY:

0.00000194

AC XY:

AN XY:

515352

show subpopulations

African (AFR)

AF:

0.0000435

AC:

AN:

22976

American (AMR)

AF:

0.00

AC:

AN:

8412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14362

East Asian (EAS)

AF:

0.00

AC:

AN:

26538

South Asian (SAS)

AF:

0.00

AC:

AN:

19744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30762

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3278

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920556

Other (OTH)

AF:

0.00

AC:

AN:

43772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

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:

2092

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

ExAC

AF:

0.0000551

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

8.8

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.14

T;T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.59

T;.;T;T

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

-0.80

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

N;.;N;.

REVEL

Benign

0.18

Sift

Uncertain

0.023

D;.;D;.

Sift4G

Benign

0.074

T;.;T;.

Polyphen

0.017

B;.;B;.

Vest4

0.083

MutPred

0.42

Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);

MVP

0.57

MPC

0.26

ClinPred

0.29

GERP RS

1.2

PromoterAI

-0.042

Neutral

(source)

Varity_R

0.036

gMVP

0.20

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs753794712

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