11-69062972-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_139075.4(TPCN2):c.635C>T(p.Ser212Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
TPCN2
NM_139075.4 missense
NM_139075.4 missense
Scores
5
9
4
Clinical Significance
Conservation
PhyloP100: 4.40
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 Likely_benign. Variant got -3 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.822
BS2
High AC in GnomAdExome4 at 33 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPCN2 | NM_139075.4 | c.635C>T | p.Ser212Leu | missense_variant | 6/25 | ENST00000294309.8 | NP_620714.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPCN2 | ENST00000294309.8 | c.635C>T | p.Ser212Leu | missense_variant | 6/25 | 1 | NM_139075.4 | ENSP00000294309 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251280Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135802
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GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461592Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727122
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74442
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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 | May 03, 2023 | The c.635C>T (p.S212L) alteration is located in exon 6 (coding exon 6) of the TPCN2 gene. This alteration results from a C to T substitution at nucleotide position 635, causing the serine (S) at amino acid position 212 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;T;D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.
Sift4G
Uncertain
D;.;D;.
Polyphen
P;.;D;.
Vest4
MutPred
Loss of phosphorylation at S212 (P = 0.0747);Loss of phosphorylation at S212 (P = 0.0747);Loss of phosphorylation at S212 (P = 0.0747);Loss of phosphorylation at S212 (P = 0.0747);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at