17-78124710-CT-TG

Variant names:

• chr17-78124710-CT-TG
• NM_001127198.5:c.704_705delAGinsCA
• TMC6 p.Lys235Thr

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001127198.5(TMC6):​c.704_705delAGinsCA​(p.Lys235Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K235R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.29
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.704_705delAGinsCA	p.Lys235Thr	missense	N/A	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.704_705delAGinsCA	p.Lys235Thr	missense	N/A	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.704_705delAGinsCA	p.Lys235Thr	missense	N/A	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.704_705delAGinsCA	p.Lys235Thr	missense	N/A	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.704_705delAGinsCA	p.Lys235Thr	missense	N/A	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.704_705delAGinsCA	p.Lys235Thr	missense	N/A	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-76120791;