chr11-69055189-C-G

Variant names:

• chr11-69055189-C-G
• rs369434788
• NM_139075.4:c.266C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_139075.4(TPCN2):​c.266C>G​(p.Thr89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T89I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1505515).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.266C>G	p.Thr89Ser	missense_variant	Exon 4 of 25	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8	c.266C>G	p.Thr89Ser	missense_variant	Exon 4 of 25	1	NM_139075.4	ENSP00000294309.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251178 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.80	T;.;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PhyloP100		0.91
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N;.;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.26	T;.;T;.
Sift4G	Uncertain	0.050	T;.;D;.
Polyphen		0.50	P;.;P;.
Vest4		0.40
MutPred		0.43		Gain of catalytic residue at T89 (P = 0.1598);Gain of catalytic residue at T89 (P = 0.1598);Gain of catalytic residue at T89 (P = 0.1598);Gain of catalytic residue at T89 (P = 0.1598);
MVP		0.69
MPC		0.18
ClinPred		0.20	T
GERP RS		-0.52
Varity_R		0.086
gMVP		0.40
Mutation Taster		=81/19	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: rs369434788; hg19: chr11-68822657;