chr11-69087895-G-A

Variant names:

• chr11-69087895-G-A
• rs3829241
• NM_139075.4:c.2201G>A

Variant summary

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

The NM_139075.4(TPCN2):​c.2201G>A​(p.Gly734Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,611,286 control chromosomes in the GnomAD database, including 106,973 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G734R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (7160 hom., cov: 32)
  • Exomes 𝑓: 0.36 (99813 hom.)
• Consequence: TPCN2 NM_139075.4 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 1.17
• Publications: 93 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=0.0012671053).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 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.2201G>A	p.Gly734Glu	missense	Exon 25 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.2201G>A	p.Gly734Glu	missense	Exon 25 of 25	ENSP00000294309.3	Q8NHX9
	ENSG00000287725	ENST00000637084.1	TSL:1	n.1058G>A		non_coding_transcript_exon	Exon 13 of 15	ENSP00000490615.1	A0A1B0GVQ7
	TPCN2	ENST00000897239.1		c.2198G>A	p.Gly733Glu	missense	Exon 25 of 25	ENSP00000567298.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42048 AN: 151896 Hom.: 7162 Cov.: 32

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.293

GnomAD2 exomes AF: 0.289 AC: 71251 AN: 246832 AF XY: 0.289

Gnomad AFR exome AF: 0.0897

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.358 AC: 522122 AN: 1459272 Hom.: 99813 Cov.: 37 AF XY: 0.352 AC XY: 255523 AN XY: 725836

African (AFR) AF: 0.0805 AC: 2692 AN: 33458

American (AMR) AF: 0.202 AC: 8999 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 6752 AN: 26102

East Asian (EAS) AF: 0.229 AC: 9080 AN: 39664

South Asian (SAS) AF: 0.128 AC: 11045 AN: 86026

European-Finnish (FIN) AF: 0.373 AC: 19713 AN: 52854

Middle Eastern (MID) AF: 0.204 AC: 1081 AN: 5308

European-Non Finnish (NFE) AF: 0.399 AC: 443651 AN: 1111044

Other (OTH) AF: 0.317 AC: 19109 AN: 60254

GnomAD4 genome AF: 0.276 AC: 42026 AN: 152014 Hom.: 7160 Cov.: 32 AF XY: 0.271 AC XY: 20152 AN XY: 74306

African (AFR) AF: 0.0957 AC: 3974 AN: 41530

American (AMR) AF: 0.254 AC: 3876 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 949 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1120 AN: 5136

South Asian (SAS) AF: 0.115 AC: 553 AN: 4824

European-Finnish (FIN) AF: 0.378 AC: 3996 AN: 10562

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26418 AN: 67908

Other (OTH) AF: 0.289 AC: 608 AN: 2106

Alfa AF: 0.340 Hom.: 30136

Bravo AF: 0.265

TwinsUK AF: 0.399 AC: 1478

ALSPAC AF: 0.423 AC: 1631

ESP6500AA AF: 0.106 AC: 466

ESP6500EA AF: 0.383 AC: 3292

ExAC AF: 0.288 AC: 34934

Asia WGS AF: 0.160 AC: 558 AN: 3478

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	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.4
DANN	Benign	0.70
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0010	B
Vest4		0.057
MPC		0.25
ClinPred		0.00058	T
GERP RS		-3.6
Varity_R		0.030
gMVP		0.32
Mutation Taster		=98/2	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: rs3829241; hg19: chr11-68855363; COSMIC: COSV53729283; COSMIC: COSV53729283;