chr17-78131988-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_152468.5(TMC8):c.256C>G(p.Arg86Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,527,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R86W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 2 hom., cov: 34)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

TMC8
NM_152468.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.306

Publications

1 publications found

Variant links:

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]

TMC8 links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
epidermodysplasia verruciformis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

TMC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009706736).

BP6

Variant 17-78131988-C-G is Benign according to our data. Variant chr17-78131988-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526235.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	NM_152468.5	MANE Select	c.256C>G	p.Arg86Gly	missense	Exon 3 of 16	NP_689681.2
	TMC6	NM_007267.7		c.-75+353G>C		intron	N/A	NP_009198.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMC8	ENST00000318430.10	TSL:1 MANE Select	c.256C>G	p.Arg86Gly	missense	Exon 3 of 16	ENSP00000325561.4
TMC6	ENST00000322914.7	TSL:1	c.-75+353G>C		intron	N/A	ENSP00000313408.2
TMC8	ENST00000589691.1	TSL:1	c.-371-371C>G		intron	N/A	ENSP00000467482.1

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000181

AC:

AN:

121866

AF XY:

0.000164

show subpopulations

Gnomad AFR exome

AF:

0.00301

Gnomad AMR exome

AF:

0.0000865

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000265

GnomAD4 exome

AF:

0.0000902

AC:

124

AN:

1375088

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

678196

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

30932

American (AMR)

AF:

0.000232

AC:

AN:

34478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24750

East Asian (EAS)

AF:

0.00

AC:

AN:

35318

South Asian (SAS)

AF:

0.0000762

AC:

AN:

78718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33336

Middle Eastern (MID)

AF:

0.00119

AC:

AN:

5034

European-Non Finnish (NFE)

AF:

0.0000112

AC:

AN:

1075186

Other (OTH)

AF:

0.000140

AC:

AN:

57336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000886

AC:

135

AN:

152318

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00277

AC:

115

AN:

41578

American (AMR)

AF:

0.000980

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00100

ExAC

AF:

0.0000631

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epidermodysplasia verruciformis (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.76

M_CAP

Benign

0.012

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

PhyloP100

-0.31

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.71

REVEL

Benign

0.0090

Sift

Benign

0.43

Sift4G

Benign

0.24

Polyphen

0.0010

Vest4

0.12

MutPred

0.43

Loss of MoRF binding (P = 0.0174)

MVP

0.35

MPC

1.3

ClinPred

0.0022

GERP RS

-0.12

PromoterAI

-0.046

Neutral

(source)

Varity_R

0.15

gMVP

0.41

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over