11-69054796-C-T

Position:

• chr11-69054796-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_139075.4(TPCN2):​c.250C>T​(p.Arg84Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000794 in 1,613,920 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: TPCN2 NM_139075.4 missense, splice_region
• Scores: Splicing: ADA: 0.001273
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.909

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004129082).
• BP6: Variant 11-69054796-C-T is Benign according to our data. Variant chr11-69054796-C-T is described in ClinVar as [Benign]. Clinvar id is 708141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0012 (183/152334) while in subpopulation EAS AF= 0.0295 (153/5188). AF 95% confidence interval is 0.0257. There are 3 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 183 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.250C>T	p.Arg84Trp	missense_variant, splice_region_variant	3/25	ENST00000294309.8	NP_620714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPCN2	ENST00000294309.8	c.250C>T	p.Arg84Trp	missense_variant, splice_region_variant	3/25	1	NM_139075.4	ENSP00000294309	P1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152216 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00217 AC: 544 AN: 250864 Hom.: 7 AF XY: 0.00200 AC XY: 271 AN XY: 135604

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0281

Gnomad SAS exome AF: 0.000426

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000752 AC: 1099 AN: 1461586 Hom.: 11 Cov.: 31 AF XY: 0.000703 AC XY: 511 AN XY: 727036

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0234

Gnomad4 SAS exome AF: 0.000569

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152334 Hom.: 3 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74494

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0295

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.00145

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 14, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.097	T;T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.90	D;.;D;D
MetaRNN	Benign	0.0041	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	-0.18	N;.;.;.
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.96	N;.;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.20	T;.;T;.
Sift4G	Benign	0.18	T;.;T;.
Polyphen		0.0020	B;.;B;.
Vest4		0.34
MVP		0.65
MPC		0.20
ClinPred		0.036	T
GERP RS		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.043
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.010		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: rs78455795; hg19: chr11-68822264;