rs3750965

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K376R) has been classified as Likely benign.

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.1127A>C	p.Lys376Thr	missense_variant	12/25	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8	c.1127A>C	p.Lys376Thr	missense_variant	12/25	1	NM_139075.4	ENSP00000294309.3

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;.;.;.
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

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: rs3750965; hg19: chr11-68840160;