11-394387-G-C

Variant names:

• chr11-394387-G-C
• rs913005931
• NM_007183.4:c.95G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007183.4(PKP3):​c.95G>C​(p.Gly32Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,490,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. G32D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: PKP3 NM_007183.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 0 publications found

Genes affected

PKP3 (HGNC:9025): (plakophilin 3) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may act in cellular desmosome-dependent adhesion and signaling pathways. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13186568).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007183.4. 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
	PKP3	NM_007183.4	MANE Select	c.95G>C	p.Gly32Ala	missense	Exon 1 of 13	NP_009114.1	Q9Y446-1
	PKP3	NM_001303029.2		c.140G>C	p.Gly47Ala	missense	Exon 2 of 14	NP_001289958.1	Q9Y446-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP3	ENST00000331563.7	TSL:1 MANE Select	c.95G>C	p.Gly32Ala	missense	Exon 1 of 13	ENSP00000331678.2	Q9Y446-1
	PKP3	ENST00000534401.6	TSL:3	c.140G>C	p.Gly47Ala	missense	Exon 2 of 14	ENSP00000434517.3	Q9Y446-2
	PKP3	ENST00000895790.1		c.95G>C	p.Gly32Ala	missense	Exon 1 of 13	ENSP00000565849.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338596 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 659530

African (AFR) AF: 0.00 AC: 0 AN: 26872

American (AMR) AF: 0.00 AC: 0 AN: 29574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23280

East Asian (EAS) AF: 0.00 AC: 0 AN: 31084

South Asian (SAS) AF: 0.00 AC: 0 AN: 74612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3948

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060286

Other (OTH) AF: 0.00 AC: 0 AN: 55566

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74354

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.087
MutPred		0.24		Gain of helix (P = 0.0143)
MVP		0.53
MPC		0.073
ClinPred		0.070	T
GERP RS		-0.14
PromoterAI		0.023	Neutral
Varity_R		0.10
gMVP		0.32
Mutation Taster		=93/7	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: rs913005931; hg19: chr11-394387;