rs2613514

Variant names:

• chr17-78114437-A-G
• rs2613514
• NM_001127198.5:c.2278-813T>C

Variant summary

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

The NM_001127198.5(TMC6):​c.2278-813T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,092 control chromosomes in the GnomAD database, including 2,132 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2132 hom., cov: 32)
• Consequence: TMC6 NM_001127198.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.194
• Publications: 11 publications found

Genes affected

TMC6 (HGNC:18021): (transmembrane channel like 6) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.2278-813T>C		intron_variant	Intron 18 of 19	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.2278-813T>C		intron_variant	Intron 18 of 19	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22105 AN: 151974 Hom.: 2131 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0935

Gnomad OTH AF: 0.125

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.146 AC: 22139 AN: 152092 Hom.: 2132 Cov.: 32 AF XY: 0.145 AC XY: 10812 AN XY: 74364

African (AFR) AF: 0.257 AC: 10677 AN: 41466

American (AMR) AF: 0.125 AC: 1906 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3472

East Asian (EAS) AF: 0.215 AC: 1111 AN: 5166

South Asian (SAS) AF: 0.214 AC: 1028 AN: 4814

European-Finnish (FIN) AF: 0.0435 AC: 461 AN: 10602

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0935 AC: 6354 AN: 67992

Other (OTH) AF: 0.123 AC: 258 AN: 2104

Alfa AF: 0.110 Hom.: 2282

Bravo AF: 0.156

Asia WGS AF: 0.230 AC: 796 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.7
DANN	Benign	0.39
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2613514; hg19: chr17-76110518;