11-69054787-G-A

Position:

• chr11-69054787-G-A

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.241G>A​(p.Val81Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000926 in 1,614,068 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.601

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=0.01028803).
• BP6: Variant 11-69054787-G-A is Benign according to our data. Variant chr11-69054787-G-A is described in ClinVar as [Benign]. Clinvar id is 783619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00498 (758/152338) while in subpopulation AFR AF= 0.0176 (731/41580). AF 95% confidence interval is 0.0165. There are 9 homozygotes in gnomad4. There are 353 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 758 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPCN2	NM_139075.4	c.241G>A	p.Val81Ile	missense_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.241G>A	p.Val81Ile	missense_variant	3/25	1	NM_139075.4	ENSP00000294309	P1

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152220 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00131 AC: 329 AN: 251106 Hom.: 3 AF XY: 0.000928 AC XY: 126 AN XY: 135732

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000504 AC: 736 AN: 1461730 Hom.: 7 Cov.: 31 AF XY: 0.000437 AC XY: 318 AN XY: 727148

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152338 Hom.: 9 Cov.: 33 AF XY: 0.00474 AC XY: 353 AN XY: 74486

Gnomad4 AFR AF: 0.0176

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000987 Hom.: 1

Bravo AF: 0.00562

ESP6500AA AF: 0.0173 AC: 76

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.0030
DANN	Benign	0.72
DEOGEN2	Benign	0.074	T;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.62	T;.;T;T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Uncertain	-0.046	T
MutationAssessor	Benign	0.050	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.050	N;.;N;.
REVEL	Benign	0.19
Sift	Benign	0.52	T;.;T;.
Sift4G	Benign	0.53	T;.;T;.
Polyphen		0.0080	B;.;B;.
Vest4		0.13
MVP		0.19
MPC		0.15
ClinPred		0.0029	T
GERP RS		-9.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.014
gMVP		0.056

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: rs116332684; hg19: chr11-68822255;