rs7208422

Positions:

• chr17-78134494-A-C
• chr17-78134494-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152468.5(TMC8):​c.917A>C​(p.Asn306Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N306I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.971

Genes affected

TMC8 (HGNC:20474): (transmembrane channel like 8) 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 8 predicted transmembrane domains and 3 leucine zipper motifs. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2173971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5	c.917A>C	p.Asn306Thr	missense_variant	8/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10	c.917A>C	p.Asn306Thr	missense_variant	8/16	1	NM_152468.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250684 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.6	N;.
REVEL	Benign	0.11
Sift	Benign	0.082	T;.
Sift4G	Uncertain	0.016	D;D
Polyphen		0.0	B;.
Vest4		0.24
MutPred		0.50		Loss of MoRF binding (P = 0.1923);.;
MVP		0.29
MPC		0.17
ClinPred		0.47	T
GERP RS		4.7
Varity_R		0.050
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7208422; hg19: chr17-76130575;