Genetic Variant EPPK1:p.Arg2364Gln (chr8-143866163-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_031308.4(EPPK1):c.7091G>A(p.Arg2364Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0043 ( 0 hom., cov: 2)

Exomes 𝑓: 0.0021 ( 9 hom. )

Failed GnomAD Quality Control

Consequence

EPPK1
NM_031308.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.309

Publications

0 publications found

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:

ENSG00000305900 (HGNC:):

ENSG00000305900 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027334511).

BP6

Variant 8-143866163-C-T is Benign according to our data. Variant chr8-143866163-C-T is described in ClinVar as Benign. ClinVar VariationId is 3034991.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00206 (828/401314) while in subpopulation AFR AF = 0.0286 (318/11118). AF 95% confidence interval is 0.026. There are 9 homozygotes in GnomAdExome4. There are 406 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031308.4. 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
	EPPK1	NM_031308.4	MANE Select	c.7091G>A	p.Arg2364Gln	missense	Exon 2 of 2	NP_112598.3	P58107

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPPK1	ENST00000615648.2	TSL:5 MANE Select	c.7091G>A	p.Arg2364Gln	missense	Exon 2 of 2	ENSP00000484472.1	P58107
EPPK1	ENST00000568225.2	TSL:6	c.7016G>A	p.Arg2339Gln	missense	Exon 1 of 1	ENSP00000456124.2	A0A075B730
ENSG00000305900	ENST00000813856.1		n.157+12924G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00435

AC:

AN:

2526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0170

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00413

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000978

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0104

AC:

2054

AN:

198012

AF XY:

0.00924

show subpopulations

Gnomad AFR exome

AF:

0.0562

Gnomad AMR exome

AF:

0.00854

Gnomad ASJ exome

AF:

0.00646

Gnomad EAS exome

AF:

0.0374

Gnomad FIN exome

AF:

0.00628

Gnomad NFE exome

AF:

0.00564

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.00206

AC:

828

AN:

401314

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

406

AN XY:

211136

show subpopulations

African (AFR)

AF:

0.0286

AC:

318

AN:

11118

American (AMR)

AF:

0.00384

AC:

AN:

15612

Ashkenazi Jewish (ASJ)

AF:

0.000967

AC:

AN:

12414

East Asian (EAS)

AF:

0.00300

AC:

AN:

26640

South Asian (SAS)

AF:

0.00121

AC:

AN:

43120

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

26672

Middle Eastern (MID)

AF:

0.00447

AC:

AN:

1788

European-Non Finnish (NFE)

AF:

0.000910

AC:

219

AN:

240630

Other (OTH)

AF:

0.00322

AC:

AN:

23320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

127

169

211

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00431

AC:

AN:

2550

Hom.:

Cov.:

AF XY:

0.00508

AC XY:

AN XY:

1182

show subpopulations

African (AFR)

AF:

0.0163

AC:

AN:

552

American (AMR)

AF:

0.00

AC:

AN:

356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00413

AC:

AN:

242

South Asian (SAS)

AF:

0.00

AC:

AN:

208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000982

AC:

AN:

1018

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.00388

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

EPPK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.034

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.76

M_CAP

Benign

0.0042

MetaRNN

Benign

0.027

MetaSVM

Benign

-1.0

PhyloP100

0.31

PrimateAI

Benign

0.20

Sift4G

Benign

0.88

Vest4

0.031

MVP

0.14

ClinPred

0.018

GERP RS

0.91

Varity_R

0.017

gMVP

0.58

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

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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