rs138959802

Variant names:

• chr12-113260373-G-A
• rs138959802
• NM_017901.6:c.118G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017901.6(TPCN1):​c.118G>A​(p.Gly40Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000241 in 1,494,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TPCN1 NM_017901.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040042162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN1	NM_017901.6	c.118G>A	p.Gly40Ser	missense_variant	Exon 3 of 28	ENST00000335509.11	NP_060371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPCN1	ENST00000335509.11	c.118G>A	p.Gly40Ser	missense_variant	Exon 3 of 28	1	NM_017901.6	ENSP00000335300.6

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

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

GnomAD2 exomes AF: 0.0000419 AC: 7 AN: 167196 AF XY: 0.0000431

Gnomad AFR exome AF: 0.000472

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000117

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 21 AN: 1342414 Hom.: 0 Cov.: 30 AF XY: 0.0000182 AC XY: 12 AN XY: 660318

African (AFR) AF: 0.000608 AC: 16 AN: 26334

American (AMR) AF: 0.00 AC: 0 AN: 21402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22726

East Asian (EAS) AF: 0.00 AC: 0 AN: 31526

South Asian (SAS) AF: 0.0000142 AC: 1 AN: 70608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5330

European-Non Finnish (NFE) AF: 0.00000378 AC: 4 AN: 1056852

Other (OTH) AF: 0.00 AC: 0 AN: 55176

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74428

African (AFR) AF: 0.000337 AC: 14 AN: 41522

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000503 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.334G>A (p.G112S) alteration is located in exon 4 (coding exon 3) of the TPCN1 gene. This alteration results from a G to A substitution at nucleotide position 334, causing the glycine (G) at amino acid position 112 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	.;T;T;.;T;T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.040	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;.;.;.;L;.;.
PhyloP100		3.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.82	N;N;N;D;N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.11	T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;T;D;T;T;T;T
Polyphen		0.026, 0.14	.;.;.;.;.;B;B;B
Vest4		0.39, 0.42, 0.47
MVP		0.59
MPC		0.40
ClinPred		0.066	T
GERP RS		3.5
PromoterAI		-0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.48
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs138959802; hg19: chr12-113698178;