rs3750965

Variant names:

• chr11-69072692-A-C
• rs3750965
• NM_139075.4:c.1127A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-69072692-A-C
• chr11-69072692-A-G

Variant summary

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

The NM_139075.4(TPCN2):​c.1127A>C​(p.Lys376Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830
• Publications: 65 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

ENSG00000287725 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.1127A>C	p.Lys376Thr	missense_variant	Exon 12 of 25	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8	c.1127A>C	p.Lys376Thr	missense_variant	Exon 12 of 25	1	NM_139075.4	ENSP00000294309.3
ENSG00000287725	ENST00000637084.1	n.-223A>C		upstream_gene_variant		1		ENSP00000490615.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.1	M;.;.;.
PhyloP100		-0.083
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D;.;D;.
REVEL	Uncertain	0.43
Sift	Benign	0.066	T;.;D;.
Sift4G	Benign	0.14	T;.;T;.
Polyphen		0.98	D;.;D;.
Vest4		0.13
MutPred		0.39		Loss of ubiquitination at K376 (P = 0.0043);Loss of ubiquitination at K376 (P = 0.0043);Loss of ubiquitination at K376 (P = 0.0043);Loss of ubiquitination at K376 (P = 0.0043);
MVP		0.74
MPC		0.28
ClinPred		0.94	D
GERP RS		2.6
Varity_R		0.24
gMVP		0.52
Mutation Taster		=80/20	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: rs3750965; hg19: chr11-68840160;