chr17-78117873-G-A

Variant names:

• chr17-78117873-G-A
• rs2613516
• NM_001127198.5:c.1950C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001127198.5(TMC6):​c.1950C>T​(p.Thr650Thr) 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:4 O:1
• Conservation: PhyloP100: 0.0930
• Publications: 10 publications found

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]

TMC6 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermodysplasia verruciformis

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1165515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127198.5. 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
	TMC6	NM_001127198.5	MANE Select	c.1950C>T	p.Thr650Thr	synonymous	Exon 16 of 20	NP_001120670.1
	TMC6	NM_001321185.1		c.1950C>T	p.Thr650Thr	synonymous	Exon 16 of 20	NP_001308114.1
	TMC6	NM_001374596.1		c.1950C>T	p.Thr650Thr	synonymous	Exon 16 of 20	NP_001361525.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	ENST00000590602.6	TSL:2 MANE Select	c.1950C>T	p.Thr650Thr	synonymous	Exon 16 of 20	ENSP00000465261.1
	TMC6	ENST00000322914.7	TSL:1	c.1950C>T	p.Thr650Thr	synonymous	Exon 16 of 20	ENSP00000313408.2
	TMC6	ENST00000392467.7	TSL:1	c.1950C>T	p.Thr650Thr	synonymous	Exon 15 of 19	ENSP00000376260.2

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

GnomAD2 exomes AF: 0.138 AC: 32183 AN: 233626 AF XY: 0.143

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 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

African (AFR) AF: 0.0247 AC: 824 AN: 33426

American (AMR) AF: 0.103 AC: 4516 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3879 AN: 25908

East Asian (EAS) AF: 0.136 AC: 5349 AN: 39446

South Asian (SAS) AF: 0.163 AC: 13848 AN: 85192

European-Finnish (FIN) AF: 0.153 AC: 7938 AN: 51826

Middle Eastern (MID) AF: 0.212 AC: 1220 AN: 5748

European-Non Finnish (NFE) AF: 0.158 AC: 175601 AN: 1108782

Other (OTH) AF: 0.153 AC: 9183 AN: 60076

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

African (AFR) AF: 0.0280 AC: 1164 AN: 41570

American (AMR) AF: 0.129 AC: 1977 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3470

East Asian (EAS) AF: 0.127 AC: 652 AN: 5152

South Asian (SAS) AF: 0.170 AC: 819 AN: 4826

European-Finnish (FIN) AF: 0.146 AC: 1552 AN: 10594

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.153 AC: 10435 AN: 67998

Other (OTH) AF: 0.127 AC: 268 AN: 2116

Alfa AF: 0.132 Hom.: 1279

Bravo AF: 0.110

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.1
DANN	Benign	0.82
PhyloP100		0.093
Mutation Taster		=99/1	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: rs2613516; hg19: chr17-76113954; COSMIC: COSV59807663; COSMIC: COSV59807663;