chr17-78113210-C-T

Variant names:

• chr17-78113210-C-T
• NM_001127198.5:c.2356G>A

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.2356G>A​(p.Val786Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.405
• 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 (MetaRNN=0.031440854).

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.2356G>A	p.Val786Ile	missense splice_region	Exon 20 of 20	NP_001120670.1	Q7Z403-1
	TMC6	NM_001321185.1		c.2356G>A	p.Val786Ile	missense splice_region	Exon 20 of 20	NP_001308114.1	Q7Z403-1
	TMC6	NM_001374596.1		c.2356G>A	p.Val786Ile	missense splice_region	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.2356G>A	p.Val786Ile	missense splice_region	Exon 20 of 20	ENSP00000465261.1	Q7Z403-1
	TMC6	ENST00000322914.7	TSL:1	c.2356G>A	p.Val786Ile	missense splice_region	Exon 20 of 20	ENSP00000313408.2	Q7Z403-1
	TMC6	ENST00000392467.7	TSL:1	c.2356G>A	p.Val786Ile	missense splice_region	Exon 19 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402050 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691732

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32246

American (AMR) AF: 0.00 AC: 0 AN: 35892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25028

East Asian (EAS) AF: 0.00 AC: 0 AN: 36862

South Asian (SAS) AF: 0.00 AC: 0 AN: 79454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079958

Other (OTH) AF: 0.00 AC: 0 AN: 58044

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.7
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.41
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.069
Sift	Benign	0.56	T
Sift4G	Benign	0.25	T
Polyphen		0.072	B
Vest4		0.030
MutPred		0.091		Gain of glycosylation at T788 (P = 0.1486)
MVP		0.19
MPC		0.13
ClinPred		0.065	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
gMVP		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.030		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

hg19: chr17-76109291;