11-69055190-C-T

Variant names:

• chr11-69055190-C-T
• rs115204200
• NM_139075.4:c.267C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_139075.4(TPCN2):​c.267C>T​(p.Thr89Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,074 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (12 hom.)
• Consequence: TPCN2 NM_139075.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.969
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-69055190-C-T is Benign according to our data. Variant chr11-69055190-C-T is described in ClinVar as Benign. ClinVar VariationId is 776634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.969 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00652 (994/152370) while in subpopulation AFR AF = 0.0229 (953/41594). AF 95% confidence interval is 0.0217. There are 9 homozygotes in GnomAd4. There are 469 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 994 AD gene.

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.267C>T	p.Thr89Thr	synonymous	Exon 4 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.267C>T	p.Thr89Thr	synonymous	Exon 4 of 25	ENSP00000294309.3	Q8NHX9
	TPCN2	ENST00000897239.1		c.267C>T	p.Thr89Thr	synonymous	Exon 4 of 25	ENSP00000567298.1
	TPCN2	ENST00000897242.1		c.267C>T	p.Thr89Thr	synonymous	Exon 4 of 25	ENSP00000567301.1

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 991 AN: 152252 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00180 AC: 453 AN: 251144 AF XY: 0.00130

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000639 AC: 934 AN: 1461704 Hom.: 12 Cov.: 31 AF XY: 0.000517 AC XY: 376 AN XY: 727184

African (AFR) AF: 0.0236 AC: 791 AN: 33468

American (AMR) AF: 0.00107 AC: 48 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111936

Other (OTH) AF: 0.00134 AC: 81 AN: 60392

GnomAD4 genome AF: 0.00652 AC: 994 AN: 152370 Hom.: 9 Cov.: 33 AF XY: 0.00629 AC XY: 469 AN XY: 74526

African (AFR) AF: 0.0229 AC: 953 AN: 41594

American (AMR) AF: 0.00176 AC: 27 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00403 Hom.: 2

Bravo AF: 0.00784

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.1
DANN	Benign	0.57
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs115204200; hg19: chr11-68822658;