11-69055236-C-T

Variant names:

• chr11-69055236-C-T
• rs2134520566
• NM_139075.4:c.313C>T

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.313C>T​(p.Leu105Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L105V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.666
• 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: 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=0.18809476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.313C>T	p.Leu105Phe	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.313C>T	p.Leu105Phe	missense_variant	Exon 4 of 25	1	NM_139075.4	ENSP00000294309.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	6.8
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	D;T;D;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.8	L;.;.;.
PhyloP100		0.67
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;.;D;.
REVEL	Uncertain	0.33
Sift	Benign	0.17	T;.;T;.
Sift4G	Benign	0.098	T;.;T;.
Polyphen		0.66	P;.;P;.
Vest4		0.095
MutPred		0.22		Gain of phosphorylation at T108 (P = 0.1086);Gain of phosphorylation at T108 (P = 0.1086);Gain of phosphorylation at T108 (P = 0.1086);Gain of phosphorylation at T108 (P = 0.1086);
MVP		0.58
MPC		0.25
ClinPred		0.75	D
GERP RS		2.5
Varity_R		0.10
gMVP		0.53
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2134520566; hg19: chr11-68822704;