NM_001127198.5:c.2380G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_001127198.5(TMC6):c.2380G>C(p.Ala794Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000822 in 1,557,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A794T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -3.94

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

epidermodysplasia verruciformis, susceptibility to, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007128954).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000361 (55/152322) while in subpopulation AFR AF = 0.00127 (53/41576). AF 95% confidence interval is 0.001. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127198.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMC6	NM_001127198.5	MANE Select	c.2380G>C	p.Ala794Pro	missense	Exon 20 of 20	NP_001120670.1	Q7Z403-1
TMC6	NM_001321185.1		c.2380G>C	p.Ala794Pro	missense	Exon 20 of 20	NP_001308114.1	Q7Z403-1
TMC6	NM_001374596.1		c.2380G>C	p.Ala794Pro	missense	Exon 20 of 20	NP_001361525.1	Q7Z403-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMC6	ENST00000590602.6	TSL:2 MANE Select	c.2380G>C	p.Ala794Pro	missense	Exon 20 of 20	ENSP00000465261.1	Q7Z403-1
TMC6	ENST00000322914.7	TSL:1	c.2380G>C	p.Ala794Pro	missense	Exon 20 of 20	ENSP00000313408.2	Q7Z403-1
TMC6	ENST00000392467.7	TSL:1	c.2380G>C	p.Ala794Pro	missense	Exon 19 of 19	ENSP00000376260.2	Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000113

AC:

AN:

167498

AF XY:

0.0000900

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.0000391

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:

0.00

GnomAD4 exome

AF:

0.0000519

AC:

AN:

1405512

Hom.:

Cov.:

AF XY:

0.0000389

AC XY:

AN XY:

693770

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

32440

American (AMR)

AF:

0.0000546

AC:

AN:

36620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

37172

South Asian (SAS)

AF:

0.00

AC:

AN:

79728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48892

Middle Eastern (MID)

AF:

0.000529

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081722

Other (OTH)

AF:

0.000189

AC:

AN:

58174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000361

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

41576

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.0000450

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.000919

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000441

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

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

0.067

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.0090

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0079

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.60

M_CAP

Benign

0.012

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-3.9

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.23

REVEL

Benign

0.099

Sift

Benign

0.26

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.091

MVP

0.14

MPC

0.21

ClinPred

0.021

GERP RS

-5.7

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.16

gMVP

0.13

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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