Variant chr11-69078931-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBA1

The NM_139075.4(TPCN2):c.1450A>T(p.Met484Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,720 control chromosomes in the GnomAD database, including 23,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

Frequency

Genomes: 𝑓 0.13 ( 1921 hom., cov: 34)

Exomes 𝑓: 0.16 ( 21696 hom. )

Consequence

TPCN2
NM_139075.4 missense

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 0.705

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a mutagenesis_site Gain of function. Increased sodium currents. (size 0) in uniprot entity TPC2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0018771589).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPCN2	NM_139075.4 linkuse as main transcript	c.1450A>T	p.Met484Leu	missense_variant	16/25	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8 linkuse as main transcript	c.1450A>T	p.Met484Leu	missense_variant	16/25	1	NM_139075.4	ENSP00000294309	P1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20381

AN:

151990

Hom.:

1920

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0334

Gnomad AMI

AF:

0.0527

Gnomad AMR

AF:

0.0873

Gnomad ASJ

AF:

0.206

Gnomad EAS

AF:

0.00637

Gnomad SAS

AF:

0.210

Gnomad FIN

AF:

0.313

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.125

GnomAD3 exomes

AF:

0.158

AC:

39647

AN:

251116

Hom.:

4072

AF XY:

0.169

AC XY:

22898

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.0329

Gnomad AMR exome

AF:

0.0597

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.00381

Gnomad SAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.182

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.164

AC:

239456

AN:

1461612

Hom.:

21696

Cov.:

AF XY:

0.167

AC XY:

121587

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0318

Gnomad4 AMR exome

AF:

0.0625

Gnomad4 ASJ exome

AF:

0.199

Gnomad4 EAS exome

AF:

0.00244

Gnomad4 SAS exome

AF:

0.220

Gnomad4 FIN exome

AF:

0.295

Gnomad4 NFE exome

AF:

0.167

Gnomad4 OTH exome

AF:

0.152

GnomAD4 genome

AF:

0.134

AC:

20385

AN:

152108

Hom.:

1921

Cov.:

AF XY:

0.141

AC XY:

10506

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0334

Gnomad4 AMR

AF:

0.0872

Gnomad4 ASJ

AF:

0.206

Gnomad4 EAS

AF:

0.00619

Gnomad4 SAS

AF:

0.210

Gnomad4 FIN

AF:

0.313

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.127

Alfa

AF:

0.171

Hom.:

842

Bravo

AF:

0.109

TwinsUK

AF:

0.153

AC:

566

ALSPAC

AF:

0.152

AC:

585

ESP6500AA

AF:

0.0350

AC:

154

ESP6500EA

AF:

0.177

AC:

1516

ExAC

AF:

0.163

AC:

19806

Asia WGS

AF:

0.123

AC:

426

AN:

3478

EpiCase

AF:

0.175

EpiControl

AF:

0.173

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Skin/hair/eye pigmentation, variation in, 10

Other:1

association, no assertion criteria provided

literature only

OMIM

May 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.10

CADD

Benign

7.8

DANN

Benign

0.69

DEOGEN2

Uncertain

0.55

D;T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.74

T;.;T;T

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.;.

MutationTaster

Benign

0.43

P;P

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.8

N;.;N;.

REVEL

Uncertain

0.35

Sift

Benign

1.0

T;.;T;.

Sift4G

Benign

0.96

T;.;T;.

Polyphen

0.0040

B;.;B;.

Vest4

0.16

MutPred

0.26

Gain of ubiquitination at K487 (P = 0.1047);Gain of ubiquitination at K487 (P = 0.1047);Gain of ubiquitination at K487 (P = 0.1047);Gain of ubiquitination at K487 (P = 0.1047);

MPC

0.18

ClinPred

0.0011

GERP RS

-3.9

Varity_R

0.13

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over