Variant 12-113266336-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017901.6(TPCN1):c.394G>A(p.Ala132Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000389 in 1,608,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

TPCN1
NM_017901.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.35

Variant links:

Genes affected

TPCN1 (HGNC:18182): (two pore segment channel 1) Voltage-gated Ca(2+) and Na+ channels have 4 homologous domains, each containing 6 transmembrane segments, S1 to S6. TPCN1 is similar to these channels, but it has only 2 domains containing S1 to S6 (Ishibashi et al., 2000 [PubMed 10753632]).[supplied by OMIM, Mar 2008]

TPCN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19772044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPCN1	NM_017901.6 link	c.394G>A	p.Ala132Thr	missense_variant	4/28	ENST00000335509.11	NP_060371.2	Q9ULQ1-1B3KSG7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPCN1	ENST00000335509.11 link	c.394G>A	p.Ala132Thr	missense_variant	4/28	1	NM_017901.6	ENSP00000335300.6		Q9ULQ1-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000179

AC:

AN:

246092

Hom.:

AF XY:

0.000165

AC XY:

AN XY:

133494

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000415

AC:

605

AN:

1456372

Hom.:

Cov.:

AF XY:

0.000395

AC XY:

286

AN XY:

724712

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000507

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000138

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000302

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2024

The c.610G>A (p.A204T) alteration is located in exon 5 (coding exon 4) of the TPCN1 gene. This alteration results from a G to A substitution at nucleotide position 610, causing the alanine (A) at amino acid position 204 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

0.070

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.58

DEOGEN2

Benign

0.35

.;T;.;.;.;T;.;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.000044

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.20

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.6

.;L;.;.;.;.;.;.

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.79

N;N;N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.68

T;T;T;T;T;T;T;T

Sift4G

Benign

0.39

T;T;T;T;T;T;T;T

Polyphen

0.45, 0.71

.;B;.;P;P;.;.;.

Vest4

0.30, 0.24, 0.28, 0.37

MVP

0.87

MPC

0.20

ClinPred

0.027

GERP RS

5.4

Varity_R

0.036

gMVP

0.28

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