11-69055236-C-G

Variant summary

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

The NM_139075.4(TPCN2):ā€‹c.313C>Gā€‹(p.Leu105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TPCN2
NM_139075.4 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.666
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]

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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=0.31473252).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPCN2NM_139075.4 linkuse as main transcriptc.313C>G p.Leu105Val 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.313C>G p.Leu105Val missense_variant 4/251 NM_139075.4 ENSP00000294309 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 06, 2022The c.313C>G (p.L105V) alteration is located in exon 4 (coding exon 4) of the TPCN2 gene. This alteration results from a C to G substitution at nucleotide position 313, causing the leucine (L) at amino acid position 105 to be replaced by a valine (V). 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
0.12
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
D;T;D;T
Eigen
Benign
-0.082
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.87
D;.;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Benign
0.31
T;T;T;T
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.7
M;.;.;.
MutationTaster
Benign
0.98
D;D
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-2.5
D;.;D;.
REVEL
Uncertain
0.47
Sift
Uncertain
0.0080
D;.;D;.
Sift4G
Uncertain
0.010
D;.;D;.
Polyphen
1.0
D;.;D;.
Vest4
0.24
MutPred
0.21
Gain of glycosylation at T106 (P = 0.0739);Gain of glycosylation at T106 (P = 0.0739);Gain of glycosylation at T106 (P = 0.0739);Gain of glycosylation at T106 (P = 0.0739);
MVP
0.61
MPC
0.58
ClinPred
0.93
D
GERP RS
2.5
Varity_R
0.14
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-68822704; API