rs2613516

chr17-78117873-G-Achr17-78117873-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001127198.5(TMC6):c.1950C>T(p.Thr650=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,606,306 control chromosomes in the GnomAD database, including 18,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T650T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1295 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17575 hom.)
• Consequence: TMC6 NM_001127198.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.0930

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 17-78117873-G-A is Benign according to our data. Variant chr17-78117873-G-A is described in ClinVar as [Benign]. Clinvar id is 1165515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78117873-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.093 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.1950C>T	p.Thr650=	synonymous_variant	16/20	ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.1950C>T	p.Thr650=	synonymous_variant	16/20	2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17595 AN: 152106 Hom.: 1295 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.138 AC: 32183 AN: 233626 Hom.: 2304 AF XY: 0.143 AC XY: 18189 AN XY: 127110

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.153 AC: 222358 AN: 1454080 Hom.: 17575 Cov.: 34 AF XY: 0.153 AC XY: 110852 AN XY: 722692

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.136

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.153

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.116 AC: 17583 AN: 152226 Hom.: 1295 Cov.: 33 AF XY: 0.116 AC XY: 8619 AN XY: 74424

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.127

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.153

Gnomad4 OTH AF: 0.127

Alfa AF: 0.132 Hom.: 973

Bravo AF: 0.110

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	7.1
Dann	Benign	0.82

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: rs2613516; hg19: chr17-76113954; COSMIC: COSV59807663; COSMIC: COSV59807663;