Genetic Variant EPPK1:p.Ala2265Ala (chr8-143866459-C-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_031308.4(EPPK1):c.6795G>C(p.Ala2265Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 1,310,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A2265A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPPK1
NM_031308.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -10.4

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP7

Synonymous conserved (PhyloP=-10.4 with no splicing effect.

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.6795G>C	p.Ala2265Ala	synonymous	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.6795G>C	p.Ala2265Ala	synonymous	Exon 2 of 2	ENSP00000484472.1	P58107
EPPK1	ENST00000568225.2	TSL:6	c.6720G>C	p.Ala2240Ala	synonymous	Exon 1 of 1	ENSP00000456124.2	A0A075B730
ENSG00000305900	ENST00000813856.1		n.157+12628G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000142

AC:

AN:

141204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000305

AC:

AN:

1310616

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

645314

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30068

American (AMR)

AF:

0.00

AC:

AN:

31560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21602

East Asian (EAS)

AF:

0.00

AC:

AN:

37000

South Asian (SAS)

AF:

0.00

AC:

AN:

73302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

0.00000195

AC:

AN:

1024692

Other (OTH)

AF:

0.0000182

AC:

AN:

54828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000142

AC:

AN:

141204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

68184

show subpopulations

African (AFR)

AF:

0.0000532

AC:

AN:

37600

American (AMR)

AF:

0.00

AC:

AN:

14104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3356

East Asian (EAS)

AF:

0.00

AC:

AN:

4724

South Asian (SAS)

AF:

0.00

AC:

AN:

3898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64886

Other (OTH)

AF:

0.00

AC:

AN:

1866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.5

(source)

DANN

Benign

0.77

PhyloP100

-10

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