NM_139075.4:c.442G>T

Variant names:

• chr11-69057590-G-T
• rs148360443
• NM_139075.4:c.442G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139075.4(TPCN2):​c.442G>T​(p.Gly148Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G148R) 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: 6.84
• Publications: 4 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139075.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPCN2	NM_139075.4	MANE Select	c.442G>T	p.Gly148Trp	missense	Exon 5 of 25	NP_620714.2	Q8NHX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPCN2	ENST00000294309.8	TSL:1 MANE Select	c.442G>T	p.Gly148Trp	missense	Exon 5 of 25	ENSP00000294309.3	Q8NHX9
	TPCN2	ENST00000897239.1		c.442G>T	p.Gly148Trp	missense	Exon 5 of 25	ENSP00000567298.1
	TPCN2	ENST00000897242.1		c.442G>T	p.Gly148Trp	missense	Exon 5 of 25	ENSP00000567301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.74		Gain of catalytic residue at L146 (P = 0.0095)
MVP		0.89
MPC		0.82
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.89
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs148360443; hg19: chr11-68825058;