chr17-78138595-C-T

Variant names:

• chr17-78138595-C-T
• rs142857824
• NM_152468.5:c.1686C>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_152468.5(TMC8):​c.1686C>T​(p.Cys562Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,962 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (29 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: TMC8 NM_152468.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-78138595-C-T is Benign according to our data. Variant chr17-78138595-C-T is described in ClinVar as Benign. ClinVar VariationId is 526262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00978 (1490/152380) while in subpopulation AFR AF = 0.0336 (1398/41596). AF 95% confidence interval is 0.0321. There are 29 homozygotes in GnomAd4. There are 732 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

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.1686C>T	p.Cys562Cys	synonymous	Exon 14 of 16	NP_689681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1686C>T	p.Cys562Cys	synonymous	Exon 14 of 16	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.1017C>T	p.Cys339Cys	synonymous	Exon 13 of 15	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.1731C>T	p.Cys577Cys	synonymous	Exon 14 of 16	ENSP00000642500.1

Frequencies

GnomAD3 genomes AF: 0.00969 AC: 1476 AN: 152262 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00267 AC: 670 AN: 251062 AF XY: 0.00211

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00103 AC: 1500 AN: 1461582 Hom.: 28 Cov.: 33 AF XY: 0.000862 AC XY: 627 AN XY: 727080

African (AFR) AF: 0.0337 AC: 1129 AN: 33480

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1112002

Other (OTH) AF: 0.00258 AC: 156 AN: 60390

GnomAD4 genome AF: 0.00978 AC: 1490 AN: 152380 Hom.: 29 Cov.: 33 AF XY: 0.00982 AC XY: 732 AN XY: 74522

African (AFR) AF: 0.0336 AC: 1398 AN: 41596

American (AMR) AF: 0.00418 AC: 64 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00474 Hom.: 10

Bravo AF: 0.0112

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.4
DANN	Benign	0.47
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism

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: rs142857824; hg19: chr17-76134676;