rs7221365

Variant names:

• chr17-78138747-C-A
• rs7221365
• NM_152468.5:c.1823+15C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-78138747-C-A
• chr17-78138747-C-G
• chr17-78138747-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152468.5(TMC8):​c.1823+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,602,978 control chromosomes in the GnomAD database, including 254,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30250 hom., cov: 34)
  • Exomes 𝑓: 0.55 (224748 hom.)
• Consequence: TMC8 NM_152468.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.16
• Publications: 13 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]

TMC8 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis, susceptibility to, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-78138747-C-A is Benign according to our data. Variant chr17-78138747-C-A is described in ClinVar as Benign. ClinVar VariationId is 403549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

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.1823+15C>A		intron	N/A	NP_689681.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1823+15C>A		intron	N/A	ENSP00000325561.4	Q8IU68-1
	TMC8	ENST00000589691.1	TSL:1	c.1154+15C>A		intron	N/A	ENSP00000467482.1	Q8IU68-2
	TMC8	ENST00000972441.1		c.1868+15C>A		intron	N/A	ENSP00000642500.1

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94523 AN: 152028 Hom.: 30191 Cov.: 34

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.594

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.648

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.580 AC: 140372 AN: 241890 AF XY: 0.575

Gnomad AFR exome AF: 0.762

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.644

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.589

Gnomad NFE exome AF: 0.562

Gnomad OTH exome AF: 0.590

GnomAD4 exome AF: 0.554 AC: 803419 AN: 1450832 Hom.: 224748 Cov.: 62 AF XY: 0.554 AC XY: 399931 AN XY: 722072

African (AFR) AF: 0.765 AC: 25601 AN: 33452

American (AMR) AF: 0.641 AC: 28625 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 16868 AN: 26104

East Asian (EAS) AF: 0.448 AC: 17785 AN: 39664

South Asian (SAS) AF: 0.539 AC: 46496 AN: 86244

European-Finnish (FIN) AF: 0.582 AC: 24982 AN: 42952

Middle Eastern (MID) AF: 0.689 AC: 3969 AN: 5762

European-Non Finnish (NFE) AF: 0.544 AC: 604394 AN: 1111688

Other (OTH) AF: 0.575 AC: 34699 AN: 60310

GnomAD4 genome AF: 0.622 AC: 94646 AN: 152146 Hom.: 30250 Cov.: 34 AF XY: 0.622 AC XY: 46288 AN XY: 74402

African (AFR) AF: 0.756 AC: 31395 AN: 41506

American (AMR) AF: 0.642 AC: 9828 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 2247 AN: 3470

East Asian (EAS) AF: 0.437 AC: 2253 AN: 5158

South Asian (SAS) AF: 0.549 AC: 2650 AN: 4826

European-Finnish (FIN) AF: 0.597 AC: 6325 AN: 10600

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37867 AN: 67972

Other (OTH) AF: 0.627 AC: 1322 AN: 2110

Alfa AF: 0.594 Hom.: 64521

Bravo AF: 0.633

Asia WGS AF: 0.532 AC: 1850 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Epidermodysplasia verruciformis (1)
-	-	1	Epidermodysplasia verruciformis, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.62
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7221365; hg19: chr17-76134828; COSMIC: COSV59209064; COSMIC: COSV59209064;