NM_139075.4:c.16G>A

Variant names:

• chr11-69049013-G-A
• rs1369232425
• NM_139075.4:c.16G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139075.4(TPCN2):​c.16G>A​(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000242 in 1,239,888 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.649
• Publications: 1 publications found

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]

TPCN2 Gene-Disease associations (from GenCC):

• albinism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13963667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.16G>A	p.Ala6Thr	missense_variant	Exon 1 of 25	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8	c.16G>A	p.Ala6Thr	missense_variant	Exon 1 of 25	1	NM_139075.4	ENSP00000294309.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1087662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 513948

African (AFR) AF: 0.00 AC: 0 AN: 23016

American (AMR) AF: 0.00 AC: 0 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14364

East Asian (EAS) AF: 0.0000377 AC: 1 AN: 26520

South Asian (SAS) AF: 0.00 AC: 0 AN: 19740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4050

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920104

Other (OTH) AF: 0.00 AC: 0 AN: 43790

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152226 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>A (p.A6T) alteration is located in exon 1 (coding exon 1) of the TPCN2 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the alanine (A) at amino acid position 6 to be replaced by a threonine (T). 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	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.1	M;.;.;.
PhyloP100		0.65
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.92	N;.;N;.
REVEL	Benign	0.21
Sift	Benign	0.033	D;.;D;.
Sift4G	Benign	0.084	T;.;T;.
Polyphen		0.28	B;.;B;.
Vest4		0.038
MutPred		0.087		Gain of glycosylation at A6 (P = 0.0589);Gain of glycosylation at A6 (P = 0.0589);Gain of glycosylation at A6 (P = 0.0589);Gain of glycosylation at A6 (P = 0.0589);
MVP		0.53
MPC		0.19
ClinPred		0.18	T
GERP RS		1.7
PromoterAI		0.0052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.059
gMVP		0.27
Mutation Taster		=95/5	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

Other links and lift over

dbSNP: rs1369232425; hg19: chr11-68816481;