11-69072692-A-G

Variant names:

• chr11-69072692-A-G
• rs3750965
• NM_139075.4:c.1127A>G

Variant summary

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

The NM_139075.4(TPCN2):​c.1127A>G​(p.Lys376Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,613,194 control chromosomes in the GnomAD database, including 81,361 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6155 hom., cov: 32)
  • Exomes 𝑓: 0.32 (75206 hom.)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830
• Publications: 65 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

ENSG00000287725 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6670098E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPCN2	NM_139075.4	MANE Select	c.1127A>G	p.Lys376Arg	missense	Exon 12 of 25	NP_620714.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPCN2	ENST00000294309.8	TSL:1 MANE Select	c.1127A>G	p.Lys376Arg	missense	Exon 12 of 25	ENSP00000294309.3
	TPCN2	ENST00000637342.1	TSL:5	c.1127A>G	p.Lys376Arg	missense	Exon 12 of 23	ENSP00000490171.1
	TPCN2	ENST00000637504.1	TSL:5	c.1127A>G	p.Lys376Arg	missense	Exon 12 of 20	ENSP00000489759.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42052 AN: 151810 Hom.: 6155 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.287 AC: 72083 AN: 251058 AF XY: 0.302

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.208

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.315 AC: 461012 AN: 1461266 Hom.: 75206 Cov.: 48 AF XY: 0.320 AC XY: 232886 AN XY: 726958

African (AFR) AF: 0.243 AC: 8129 AN: 33474

American (AMR) AF: 0.170 AC: 7611 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 8216 AN: 26128

East Asian (EAS) AF: 0.224 AC: 8910 AN: 39692

South Asian (SAS) AF: 0.450 AC: 38780 AN: 86234

European-Finnish (FIN) AF: 0.220 AC: 11689 AN: 53116

Middle Eastern (MID) AF: 0.344 AC: 1964 AN: 5712

European-Non Finnish (NFE) AF: 0.321 AC: 356611 AN: 1111834

Other (OTH) AF: 0.316 AC: 19102 AN: 60372

GnomAD4 genome AF: 0.277 AC: 42079 AN: 151928 Hom.: 6155 Cov.: 32 AF XY: 0.273 AC XY: 20234 AN XY: 74234

African (AFR) AF: 0.243 AC: 10084 AN: 41420

American (AMR) AF: 0.216 AC: 3296 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1115 AN: 5126

South Asian (SAS) AF: 0.454 AC: 2188 AN: 4818

European-Finnish (FIN) AF: 0.202 AC: 2140 AN: 10582

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.313 AC: 21236 AN: 67920

Other (OTH) AF: 0.286 AC: 604 AN: 2110

Alfa AF: 0.305 Hom.: 22685

Bravo AF: 0.271

TwinsUK AF: 0.339 AC: 1258

ALSPAC AF: 0.323 AC: 1243

ESP6500AA AF: 0.245 AC: 1078

ESP6500EA AF: 0.316 AC: 2710

ExAC AF: 0.293 AC: 35612

Asia WGS AF: 0.303 AC: 1056 AN: 3478

EpiCase AF: 0.321

EpiControl AF: 0.320

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	5.3
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.00027	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	M
PhyloP100		-0.083
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.23
Sift	Benign	0.50	T
Sift4G	Benign	0.41	T
Polyphen		0.29	B
Vest4		0.052
MPC		0.16
ClinPred		0.011	T
GERP RS		2.6
Varity_R		0.052
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3750965; hg19: chr11-68840160; COSMIC: COSV53728686; COSMIC: COSV53728686;