11-69055302-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_139075.4(TPCN2):​c.379A>T​(p.Ser127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TPCN2
NM_139075.4 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.730
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPCN2NM_139075.4 linkuse as main transcriptc.379A>T p.Ser127Cys missense_variant 4/25 ENST00000294309.8 NP_620714.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPCN2ENST00000294309.8 linkuse as main transcriptc.379A>T p.Ser127Cys missense_variant 4/251 NM_139075.4 ENSP00000294309 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250108
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135284
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000580
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:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461276
Hom.:
0
Cov.:
37
AF XY:
0.00000825
AC XY:
6
AN XY:
727020
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152194
Hom.:
0
Cov.:
35
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.00000825
AC:
1

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 GeneticsSep 26, 2023The c.379A>T (p.S127C) alteration is located in exon 4 (coding exon 4) of the TPCN2 gene. This alteration results from a A to T substitution at nucleotide position 379, causing the serine (S) at amino acid position 127 to be replaced by a cysteine (C). 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
0.10
BayesDel_addAF
Uncertain
0.066
T
BayesDel_noAF
Uncertain
0.030
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.80
D;T;D;T
Eigen
Benign
0.042
Eigen_PC
Benign
-0.15
FATHMM_MKL
Benign
0.72
D
LIST_S2
Uncertain
0.94
D;.;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.65
D;D;D;D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Uncertain
2.8
M;.;.;.
MutationTaster
Benign
0.97
N;N
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.9
D;.;D;.
REVEL
Uncertain
0.46
Sift
Benign
0.031
D;.;T;.
Sift4G
Uncertain
0.019
D;.;D;.
Polyphen
1.0
D;.;D;.
Vest4
0.36
MutPred
0.60
Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);
MVP
0.80
MPC
0.69
ClinPred
0.84
D
GERP RS
1.0
Varity_R
0.15
gMVP
0.64

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: rs768909741; hg19: chr11-68822770; API