12-113226881-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000335509.11(TPCN1):ā€‹c.29C>Gā€‹(p.Pro10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.000031 ( 0 hom. )

Consequence

TPCN1
ENST00000335509.11 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.31947684).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPCN1NM_017901.6 linkuse as main transcriptc.29C>G p.Pro10Arg missense_variant 2/28 ENST00000335509.11 NP_060371.2 Q9ULQ1-1B3KSG7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPCN1ENST00000335509.11 linkuse as main transcriptc.29C>G p.Pro10Arg missense_variant 2/281 NM_017901.6 ENSP00000335300.6 Q9ULQ1-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
33
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251194
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135870
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000315
AC:
46
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.0000275
AC XY:
20
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsApr 13, 2023The c.245C>G (p.P82R) alteration is located in exon 3 (coding exon 2) of the TPCN1 gene. This alteration results from a C to G substitution at nucleotide position 245, causing the proline (P) at amino acid position 82 to be replaced by an arginine (R). 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
Pathogenic
0.86
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;T;.;T;.;T;.;.;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.92
D;D;D;D;.;D;.;T;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.32
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.9
.;.;.;.;.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.0
D;N;D;D;D;N;N;D;N
REVEL
Benign
0.24
Sift
Uncertain
0.0040
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.012
D;D;D;D;D;D;D;D;D
Polyphen
0.98, 0.98
.;.;.;.;.;D;D;.;D
Vest4
0.52, 0.43, 0.45
MutPred
0.45
.;.;Gain of sheet (P = 0.0061);.;Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);.;Gain of sheet (P = 0.0061);.;
MVP
0.72
MPC
0.77
ClinPred
0.58
D
GERP RS
4.0
Varity_R
0.16
gMVP
0.55

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.

Other links and lift over

dbSNP: rs150945178; hg19: chr12-113664686; API