17-78113277-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127198.5(TMC6):c.2355-66C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,499,028 control chromosomes in the GnomAD database, including 22,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3819 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19177 hom.)
• Consequence: TMC6 NM_001127198.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.266

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-78113277-G-A is Benign according to our data. Variant chr17-78113277-G-A is described in ClinVar as [Benign]. Clinvar id is 1279056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC6	NM_001127198.5	c.2355-66C>T		intron_variant		ENST00000590602.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC6	ENST00000590602.6	c.2355-66C>T		intron_variant		2	NM_001127198.5	P1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31447 AN: 152092 Hom.: 3809 Cov.: 33

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.206

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.196

GnomAD4 exome AF: 0.160 AC: 216109 AN: 1346818 Hom.: 19177 AF XY: 0.164 AC XY: 108438 AN XY: 662570

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.184

GnomAD4 genome AF: 0.207 AC: 31502 AN: 152210 Hom.: 3819 Cov.: 33 AF XY: 0.208 AC XY: 15476 AN XY: 74418

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.206

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.201

Alfa AF: 0.143 Hom.: 893

Bravo AF: 0.220

Asia WGS AF: 0.304 AC: 1053 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 42% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	5.1
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs910557; hg19: chr17-76109358; COSMIC: COSV56944639; COSMIC: COSV56944639;