17-78113203-G-A

Variant names:

• chr17-78113203-G-A
• rs2073878430
• NM_001127198.5:c.2363C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127198.5(TMC6):​c.2363C>T​(p.Thr788Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,403,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.179

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06496605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.2363C>T	p.Thr788Ile	missense_variant	Exon 20 of 20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.2363C>T	p.Thr788Ile	missense_variant	Exon 20 of 20	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000121 AC: 17 AN: 1403566 Hom.: 0 Cov.: 31 AF XY: 0.00000866 AC XY: 6 AN XY: 692574

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2363C>T (p.T788I) alteration is located in exon 20 (coding exon 19) of the TMC6 gene. This alteration results from a C to T substitution at nucleotide position 2363, causing the threonine (T) at amino acid position 788 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.1
DANN	Benign	0.81
DEOGEN2	Benign	0.0091	T;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	.;.;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.065	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N;N;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.58	.;N;N;N;.
REVEL	Benign	0.054
Sift	Benign	0.39	.;T;T;D;.
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.012	B;B;B;P;B
Vest4		0.049
MutPred		0.22		Loss of phosphorylation at T788 (P = 0.0083);Loss of phosphorylation at T788 (P = 0.0083);Loss of phosphorylation at T788 (P = 0.0083);.;.;
MVP		0.17
MPC		0.20
ClinPred		0.14	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2073878430; hg19: chr17-76109284;