chr17-78131619-C-G

Variant names:

• chr17-78131619-C-G
• rs1222145664
• NM_152468.5:c.31C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152468.5(TMC8):​c.31C>G​(p.Arg11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMC8 NM_152468.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37
• Publications: 0 publications found

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]

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.06559044).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152468.5. 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
	TMC8	NM_152468.5	MANE Select	c.31C>G	p.Arg11Gly	missense	Exon 2 of 16	NP_689681.2
	TMC6	NM_007267.7		c.-75+722G>C		intron	N/A	NP_009198.4	Q7Z403-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.31C>G	p.Arg11Gly	missense	Exon 2 of 16	ENSP00000325561.4	Q8IU68-1
	TMC6	ENST00000322914.7	TSL:1	c.-75+722G>C		intron	N/A	ENSP00000313408.2	Q7Z403-1
	TMC8	ENST00000589691.1	TSL:1	c.-372+214C>G		intron	N/A	ENSP00000467482.1	Q8IU68-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000678 AC: 1 AN: 147546 AF XY: 0.0000126

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398168 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 689996

African (AFR) AF: 0.00 AC: 0 AN: 31792

American (AMR) AF: 0.00 AC: 0 AN: 35958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 36068

South Asian (SAS) AF: 0.00 AC: 0 AN: 79370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4908

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080426

Other (OTH) AF: 0.00 AC: 0 AN: 57958

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Benign	0.24	T
Sift4G	Benign	0.086	T
Polyphen		0.016	B
Vest4		0.031
MutPred		0.15		Gain of loop (P = 0.0502)
MVP		0.24
MPC		1.3
ClinPred		0.066	T
GERP RS		1.5
Varity_R		0.11
gMVP		0.47

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

Other links and lift over

dbSNP: rs1222145664; hg19: chr17-76127700;