11-69067500-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_139075.4(TPCN2):​c.727-3T>A variant causes a splice region, intron 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. 2/3 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: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPCN2 NM_139075.4 splice_region, intron
• Scores: Splicing: ADA: 0.01018
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460508 Hom.: 0 Cov.: 42 AF XY: 0.00000138 AC XY: 1 AN XY: 726576

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.41
PhyloP100		-3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.010
dbscSNV1_RF	Benign	0.33
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6591368; hg19: chr11-68834968;