Genetic Variant EPPK1:p.Thr2269Thr (chr8-143866447-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_031308.4(EPPK1):c.6807C>T(p.Thr2269Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000686 in 1,399,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

EPPK1
NM_031308.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.61

Variant links:

Genes affected

EPPK1 (HGNC:15577): (epiplakin 1) The protein encoded by this gene belongs to the plakin family of proteins, which play a role in the organization of cytoskeletal architecture. This family member is composed of several highly homologous plakin repeats. It may function to maintain the integrity of keratin intermediate filament networks in epithelial cells. Studies of the orthologous mouse protein suggest that it accelerates keratinocyte migration during wound healing. [provided by RefSeq, Oct 2013]

EPPK1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 8-143866447-G-A is Benign according to our data. Variant chr8-143866447-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3039843.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-5.61 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPPK1	NM_031308.4 link	c.6807C>T	p.Thr2269Thr	synonymous_variant	Exon 2 of 2	ENST00000615648.2	NP_112598.3	P58107

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPPK1	ENST00000615648.2 link	c.6807C>T	p.Thr2269Thr	synonymous_variant	Exon 2 of 2	5	NM_031308.4	ENSP00000484472.1		P58107
EPPK1	ENST00000568225.2 link	c.6732C>T	p.Thr2244Thr	synonymous_variant	Exon 1 of 1	6		ENSP00000456124.2		A0A075B730

Frequencies

GnomAD3 genomes

AF:

0.000101

AC:

AN:

138736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000216

Gnomad SAS

AF:

0.000265

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00331

Gnomad NFE

AF:

0.0000936

Gnomad OTH

AF:

0.000551

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

243714

Hom.:

AF XY:

0.0000301

AC XY:

AN XY:

132788

show subpopulations

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:

0.0000997

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1261066

Hom.:

Cov.:

AF XY:

0.0000790

AC XY:

AN XY:

620258

show subpopulations

Gnomad4 AFR exome

AF:

0.000104

Gnomad4 AMR exome

AF:

0.0000681

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000557

Gnomad4 SAS exome

AF:

0.000114

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000628

Gnomad4 OTH exome

AF:

0.0000942

GnomAD4 genome

AF:

0.000101

AC:

AN:

138852

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

67022

show subpopulations

Gnomad4 AFR

AF:

0.000109

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000216

Gnomad4 SAS

AF:

0.000266

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000936

Gnomad4 OTH

AF:

0.000545

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

EPPK1-related disorder

Benign:1

May 11, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.8

DANN

Benign

0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over