rs80354176

Positions:

• chr17-78124711-T-C
• chr17-78124711-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127198.5(TMC6):​c.704A>G​(p.Lys235Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0016 in 1,596,534 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (60 hom.)
• Consequence: TMC6 NM_001127198.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.29

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045574605).
• BP6: Variant 17-78124711-T-C is Benign according to our data. Variant chr17-78124711-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 456016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78124711-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5	c.704A>G	p.Lys235Arg	missense_variant	8/20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6	c.704A>G	p.Lys235Arg	missense_variant	8/20	2	NM_001127198.5	ENSP00000465261.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152190 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00504 AC: 1080 AN: 214148 Hom.: 41 AF XY: 0.00458 AC XY: 534 AN XY: 116618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0675

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00156 AC: 2248 AN: 1444226 Hom.: 60 Cov.: 33 AF XY: 0.00151 AC XY: 1085 AN XY: 717038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000960

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0523

Gnomad4 SAS exome AF: 0.000570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000543

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152308 Hom.: 6 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0544

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.00238

ExAC AF: 0.00407 AC: 491

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epidermodysplasia verruciformis, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 23, 2021

- -

Epidermodysplasia verruciformis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;.;D;D;D;D
MetaRNN	Benign	0.0046	T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.9	M;M;M;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	.;N;N;N;.;.
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	.;D;D;D;.;.
Sift4G	Uncertain	0.027	D;D;D;D;D;.
Polyphen		0.99	D;D;D;D;D;.
Vest4		0.80
MVP		0.63
MPC		0.59
ClinPred		0.097	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.37
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs80354176; hg19: chr17-76120792; COSMIC: COSV59811501; COSMIC: COSV59811501;