17-78112992-C-A

Variant names:

• chr17-78112992-C-A
• rs2253277
• NM_001127198.5:c.*156G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127198.5(TMC6):​c.*156G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 645,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TMC6 NM_001127198.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144
• Publications: 0 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: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• epidermodysplasia verruciformis

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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.*156G>T		3_prime_UTR	Exon 20 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.*156G>T		3_prime_UTR	Exon 20 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.*156G>T		3_prime_UTR	Exon 20 of 20	NP_001361525.1	Q7Z403-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC6	ENST00000590602.6	TSL:2 MANE Select	c.*156G>T		3_prime_UTR	Exon 20 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.*156G>T		3_prime_UTR	Exon 20 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.*156G>T		3_prime_UTR	Exon 19 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000155 AC: 1 AN: 645504 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 338210

African (AFR) AF: 0.00 AC: 0 AN: 17096

American (AMR) AF: 0.00 AC: 0 AN: 28992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17524

East Asian (EAS) AF: 0.00 AC: 0 AN: 32300

South Asian (SAS) AF: 0.00 AC: 0 AN: 57690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2838

European-Non Finnish (NFE) AF: 0.00000237 AC: 1 AN: 421232

Other (OTH) AF: 0.00 AC: 0 AN: 33000

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.8
DANN	Benign	0.79
PhyloP100		0.14
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2253277; hg19: chr17-76109073;