11-69078931-A-T

Variant names:

• chr11-69078931-A-T
• rs35264875
• NM_139075.4:c.1450A>T

Variant summary

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

The NM_139075.4(TPCN2):​c.1450A>T​(p.Met484Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,613,720 control chromosomes in the GnomAD database, including 23,617 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1921 hom., cov: 34)
  • Exomes 𝑓: 0.16 (21696 hom.)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.705
• Publications: 89 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=0.0018771589).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPCN2	NM_139075.4	MANE Select	c.1450A>T	p.Met484Leu	missense	Exon 16 of 25	NP_620714.2	Q8NHX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPCN2	ENST00000294309.8	TSL:1 MANE Select	c.1450A>T	p.Met484Leu	missense	Exon 16 of 25	ENSP00000294309.3	Q8NHX9
	ENSG00000287725	ENST00000637084.1	TSL:1	n.307A>T		non_coding_transcript_exon	Exon 4 of 15	ENSP00000490615.1	A0A1B0GVQ7
	TPCN2	ENST00000897239.1		c.1447A>T	p.Met483Leu	missense	Exon 16 of 25	ENSP00000567298.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20381 AN: 151990 Hom.: 1920 Cov.: 34

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.0873

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.00637

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.158 AC: 39647 AN: 251116 AF XY: 0.169

Gnomad AFR exome AF: 0.0329

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.205

Gnomad EAS exome AF: 0.00381

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.164 AC: 239456 AN: 1461612 Hom.: 21696 Cov.: 70 AF XY: 0.167 AC XY: 121587 AN XY: 727082

African (AFR) AF: 0.0318 AC: 1065 AN: 33478

American (AMR) AF: 0.0625 AC: 2796 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5189 AN: 26122

East Asian (EAS) AF: 0.00244 AC: 97 AN: 39698

South Asian (SAS) AF: 0.220 AC: 18974 AN: 86254

European-Finnish (FIN) AF: 0.295 AC: 15718 AN: 53302

Middle Eastern (MID) AF: 0.210 AC: 1213 AN: 5768

European-Non Finnish (NFE) AF: 0.167 AC: 185221 AN: 1111882

Other (OTH) AF: 0.152 AC: 9183 AN: 60390

GnomAD4 genome AF: 0.134 AC: 20385 AN: 152108 Hom.: 1921 Cov.: 34 AF XY: 0.141 AC XY: 10506 AN XY: 74346

African (AFR) AF: 0.0334 AC: 1386 AN: 41524

American (AMR) AF: 0.0872 AC: 1332 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 713 AN: 3466

East Asian (EAS) AF: 0.00619 AC: 32 AN: 5168

South Asian (SAS) AF: 0.210 AC: 1014 AN: 4818

European-Finnish (FIN) AF: 0.313 AC: 3307 AN: 10552

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12240 AN: 67984

Other (OTH) AF: 0.127 AC: 269 AN: 2110

Alfa AF: 0.171 Hom.: 842

Bravo AF: 0.109

TwinsUK AF: 0.153 AC: 566

ALSPAC AF: 0.152 AC: 585

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.177 AC: 1516

ExAC AF: 0.163 AC: 19806

Asia WGS AF: 0.123 AC: 426 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.173

ClinVar

ClinVar submissions

Significance: association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	SKIN/HAIR/EYE PIGMENTATION, VARIATION IN, 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	7.8
DANN	Benign	0.69
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.70
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	0.96	T
Polyphen		0.0040	B
Vest4		0.16
MutPred		0.26		Gain of ubiquitination at K487 (P = 0.1047)
MPC		0.18
ClinPred		0.0011	T
GERP RS		-3.9
Varity_R		0.13
gMVP		0.49
Mutation Taster		=96/4	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: rs35264875; hg19: chr11-68846399; COSMIC: COSV53728164; COSMIC: COSV53728164;