rs142857824

chr17-78138595-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_152468.5(TMC8):c.1686C>T(p.Cys562=) 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, single submitter B:1
• Conservation: PhyloP100: -1.49

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]

ACMG classification

Verdict is Benign. Variant got -15 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 id is 526262.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.1686C>T	p.Cys562=	synonymous_variant	14/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.1686C>T	p.Cys562=	synonymous_variant	14/16	1	NM_152468.5	P2

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

GnomAD3 exomes AF: 0.00267 AC: 670 AN: 251062 Hom.: 13 AF XY: 0.00211 AC XY: 286 AN XY: 135730

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00258

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

Gnomad4 AFR AF: 0.0336

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00513 Hom.: 9

Bravo AF: 0.0112

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.4
Dann	Benign	0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs142857824; hg19: chr17-76134676;