11-69049065-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_139075.4(TPCN2):​c.68C>T​(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000563 in 1,242,574 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 (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

TPCN2
NM_139075.4 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.802
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.20602015).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPCN2NM_139075.4 linkuse as main transcriptc.68C>T p.Pro23Leu missense_variant 1/25 ENST00000294309.8 NP_620714.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPCN2ENST00000294309.8 linkuse as main transcriptc.68C>T p.Pro23Leu missense_variant 1/251 NM_139075.4 ENSP00000294309 P1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152174
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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
GnomAD4 exome
AF:
0.00000183
AC:
2
AN:
1090400
Hom.:
0
Cov.:
31
AF XY:
0.00000194
AC XY:
1
AN XY:
515352
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000238
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152174
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000262
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:
0.0000567

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 GeneticsNov 22, 2021The c.68C>T (p.P23L) alteration is located in exon 1 (coding exon 1) of the TPCN2 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the proline (P) at amino acid position 23 to be replaced by a leucine (L). 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
0.11
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
8.5
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T;T;T;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.073
N
LIST_S2
Benign
0.71
T;.;T;T
M_CAP
Pathogenic
0.51
D
MetaRNN
Benign
0.21
T;T;T;T
MetaSVM
Uncertain
0.043
D
MutationAssessor
Benign
1.5
L;.;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-2.2
N;.;D;.
REVEL
Uncertain
0.29
Sift
Uncertain
0.026
D;.;D;.
Sift4G
Benign
0.071
T;.;D;.
Polyphen
0.95
P;.;P;.
Vest4
0.091
MutPred
0.38
Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP
0.64
MPC
0.20
ClinPred
0.46
T
GERP RS
1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.039
gMVP
0.27

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: rs753794712; hg19: chr11-68816533; COSMIC: COSV53733890; API