chr11-69067500-T-C

Variant names:

• chr11-69067500-T-C
• rs6591368
• NM_139075.4:c.727-3T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139075.4(TPCN2):​c.727-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.979 in 1,612,790 control chromosomes in the GnomAD database, including 775,195 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.94 (67735 hom., cov: 34)
  • Exomes 𝑓: 0.98 (707460 hom.)
• Consequence: TPCN2 NM_139075.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006136
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.87
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.727-3T>C		splice_region_variant, intron_variant	Intron 7 of 24	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8	c.727-3T>C		splice_region_variant, intron_variant	Intron 7 of 24	1	NM_139075.4	ENSP00000294309.3

Frequencies

GnomAD3 genomes AF: 0.940 AC: 143117 AN: 152178 Hom.: 67689 Cov.: 34

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.927

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.952

GnomAD2 exomes AF: 0.958 AC: 239154 AN: 249760 AF XY: 0.962

Gnomad AFR exome AF: 0.832

Gnomad AMR exome AF: 0.918

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.858

Gnomad FIN exome AF: 0.994

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.983 AC: 1436388 AN: 1460494 Hom.: 707460 Cov.: 42 AF XY: 0.983 AC XY: 714364 AN XY: 726568

African (AFR) AF: 0.825 AC: 27606 AN: 33474

American (AMR) AF: 0.921 AC: 41180 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 25995 AN: 26130

East Asian (EAS) AF: 0.873 AC: 34674 AN: 39698

South Asian (SAS) AF: 0.937 AC: 80798 AN: 86250

European-Finnish (FIN) AF: 0.994 AC: 51953 AN: 52250

Middle Eastern (MID) AF: 0.988 AC: 5691 AN: 5760

European-Non Finnish (NFE) AF: 0.998 AC: 1109849 AN: 1111836

Other (OTH) AF: 0.971 AC: 58642 AN: 60378

GnomAD4 genome AF: 0.940 AC: 143222 AN: 152296 Hom.: 67735 Cov.: 34 AF XY: 0.940 AC XY: 69991 AN XY: 74470

African (AFR) AF: 0.835 AC: 34671 AN: 41530

American (AMR) AF: 0.945 AC: 14467 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3465 AN: 3472

East Asian (EAS) AF: 0.865 AC: 4473 AN: 5172

South Asian (SAS) AF: 0.927 AC: 4475 AN: 4828

European-Finnish (FIN) AF: 0.994 AC: 10570 AN: 10630

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67899 AN: 68036

Other (OTH) AF: 0.950 AC: 2011 AN: 2116

Alfa AF: 0.974 Hom.: 37566

Bravo AF: 0.932

Asia WGS AF: 0.880 AC: 3062 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.40
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.020
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: rs6591368; hg19: chr11-68834968;