8-143866598-T-G

Variant names:

• chr8-143866598-T-G
• rs1586685875
• NM_031308.4:c.6656A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_031308.4(EPPK1):​c.6656A>C​(p.Tyr2219Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2219F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 26)
• Consequence: EPPK1 NM_031308.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

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]

ENSG00000305900 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34282076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPPK1	NM_031308.4	c.6656A>C	p.Tyr2219Ser	missense_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.6656A>C	p.Tyr2219Ser	missense_variant	Exon 2 of 2	5	NM_031308.4	ENSP00000484472.1
EPPK1	ENST00000568225.2	c.6581A>C	p.Tyr2194Ser	missense_variant	Exon 1 of 1	6		ENSP00000456124.2
ENSG00000305900	ENST00000813856.1	n.157+12489A>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		3.2
PrimateAI	Uncertain	0.50	T
Sift4G	Uncertain	0.035	D;D
Vest4		0.27
MutPred		0.64		Gain of disorder (P = 0.0017);.;
MVP		0.62
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.12
gMVP		0.88
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1586685875; hg19: chr8-144940766;