chr8-143866543-G-A

Variant names:

• chr8-143866543-G-A
• rs1366613440
• NM_031308.4:c.6711C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_031308.4(EPPK1):​c.6711C>T​(p.Pro2237Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,596,718 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0081 (22 hom., cov: 26)
  • Exomes 𝑓: 0.00091 (18 hom.)
• Consequence: EPPK1 NM_031308.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.16

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]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 8-143866543-G-A is Benign according to our data. Variant chr8-143866543-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3034987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00809 (1228/151822) while in subpopulation AFR AF = 0.0284 (1175/41416). AF 95% confidence interval is 0.027. There are 22 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPPK1	NM_031308.4	c.6711C>T	p.Pro2237Pro	synonymous_variant	Exon 2 of 2	ENST00000615648.2	NP_112598.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPPK1	ENST00000615648.2	c.6711C>T	p.Pro2237Pro	synonymous_variant	Exon 2 of 2	5	NM_031308.4	ENSP00000484472.1
EPPK1	ENST00000568225.2	c.6636C>T	p.Pro2212Pro	synonymous_variant	Exon 1 of 1	6		ENSP00000456124.2

Frequencies

GnomAD3 genomes AF: 0.00808 AC: 1226 AN: 151704 Hom.: 22 Cov.: 26

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00770

GnomAD2 exomes AF: 0.000890 AC: 220 AN: 247086 AF XY: 0.000610

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000907 AC: 1311 AN: 1444896 Hom.: 18 Cov.: 31 AF XY: 0.000808 AC XY: 580 AN XY: 718016

Gnomad4 AFR exome AF: 0.0329 AC: 1082 AN: 32916

Gnomad4 AMR exome AF: 0.000747 AC: 32 AN: 42810

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25208

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39610

Gnomad4 SAS exome AF: 0.000107 AC: 9 AN: 84324

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49904

Gnomad4 NFE exome AF: 0.0000787 AC: 87 AN: 1104790

Gnomad4 Remaining exome AF: 0.00166 AC: 99 AN: 59680

GnomAD4 genome AF: 0.00809 AC: 1228 AN: 151822 Hom.: 22 Cov.: 26 AF XY: 0.00731 AC XY: 542 AN XY: 74178

Gnomad4 AFR AF: 0.0284 AC: 0.0283707 AN: 0.0283707

Gnomad4 AMR AF: 0.00170 AC: 0.00170402 AN: 0.00170402

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000833 AC: 0.000832986 AN: 0.000832986

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000103 AC: 0.000103105 AN: 0.000103105

Gnomad4 OTH AF: 0.00762 AC: 0.00761905 AN: 0.00761905

Alfa AF: 0.00649 Hom.: 2

Bravo AF: 0.00930

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EPPK1-related disorder Benign:1

May 17, 2022

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	-0.70
CADD	Benign	9.4
DANN	Benign	0.94

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

Other links and lift over

dbSNP: rs1366613440; hg19: chr8-144940711;