rs8068430

Variant names:

• chr17-78136611-T-C
• rs8068430
• NM_152468.5:c.1128-624T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_152468.5(TMC8):​c.1128-624T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 172,348 control chromosomes in the GnomAD database, including 3,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2765 hom., cov: 33)
  • Exomes 𝑓: 0.17 (368 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.812
• Publications: 13 publications found

Genes affected

TMC8 (HGNC:20474): (transmembrane channel like 8) 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 8 predicted transmembrane domains and 3 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC8 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-78136611-T-C is Benign according to our data. Variant chr17-78136611-T-C is described in ClinVar as Benign. ClinVar VariationId is 2688349.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152468.5. 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
	TMC8	NM_152468.5	MANE Select	c.1128-624T>C		intron	N/A	NP_689681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1128-624T>C		intron	N/A	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.459-624T>C		intron	N/A	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.1173-624T>C		intron	N/A	ENSP00000642500.1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28322 AN: 152082 Hom.: 2757 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.169 AC: 3411 AN: 20148 Hom.: 368 Cov.: 0 AF XY: 0.180 AC XY: 1940 AN XY: 10778

African (AFR) AF: 0.126 AC: 36 AN: 286

American (AMR) AF: 0.147 AC: 457 AN: 3108

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 40 AN: 224

East Asian (EAS) AF: 0.166 AC: 202 AN: 1218

South Asian (SAS) AF: 0.255 AC: 936 AN: 3672

European-Finnish (FIN) AF: 0.110 AC: 41 AN: 374

Middle Eastern (MID) AF: 0.262 AC: 11 AN: 42

European-Non Finnish (NFE) AF: 0.149 AC: 1543 AN: 10364

Other (OTH) AF: 0.169 AC: 145 AN: 860

GnomAD4 genome AF: 0.186 AC: 28362 AN: 152200 Hom.: 2765 Cov.: 33 AF XY: 0.190 AC XY: 14126 AN XY: 74420

African (AFR) AF: 0.162 AC: 6725 AN: 41512

American (AMR) AF: 0.162 AC: 2482 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 987 AN: 3468

East Asian (EAS) AF: 0.224 AC: 1161 AN: 5190

South Asian (SAS) AF: 0.286 AC: 1382 AN: 4824

European-Finnish (FIN) AF: 0.216 AC: 2289 AN: 10588

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.184 AC: 12508 AN: 67994

Other (OTH) AF: 0.218 AC: 462 AN: 2116

Alfa AF: 0.189 Hom.: 7123

Bravo AF: 0.179

Asia WGS AF: 0.267 AC: 927 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.39
DANN	Benign	0.34
PhyloP100		-0.81
Mutation Taster		=100/0	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: rs8068430; hg19: chr17-76132692;