11-396866-G-T

Variant names:

• chr11-396866-G-T
• rs574418224
• NM_007183.4:c.365G>T

Variant summary

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

The NM_007183.4(PKP3):​c.365G>T​(p.Arg122Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 1,599,450 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R122H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: PKP3 NM_007183.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.365G>T	p.Arg122Leu	missense	Exon 3 of 13	NP_009114.1	Q9Y446-1
	PKP3	NM_001303029.2		c.410G>T	p.Arg137Leu	missense	Exon 4 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.365G>T	p.Arg122Leu	missense	Exon 3 of 13	ENSP00000331678.2	Q9Y446-1
	PKP3	ENST00000534401.6	TSL:3	c.410G>T	p.Arg137Leu	missense	Exon 4 of 14	ENSP00000434517.3	Q9Y446-2
	PKP3	ENST00000895790.1		c.365G>T	p.Arg122Leu	missense	Exon 3 of 13	ENSP00000565849.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 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

GnomAD2 exomes AF: 0.0000182 AC: 4 AN: 219630 AF XY: 0.0000165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1447146 Hom.: 0 Cov.: 34 AF XY: 0.00000834 AC XY: 6 AN XY: 719536

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.000136 AC: 6 AN: 43962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 84972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108312

Other (OTH) AF: 0.0000167 AC: 1 AN: 59932

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152304 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74476

⚠️ 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: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ 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: 0.0000378

ExAC AF: 0.0000167 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.90	L
PhyloP100		2.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.42		Loss of MoRF binding (P = 0.0045)
MVP		0.88
MPC		0.45
ClinPred		0.66	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.33
gMVP		0.64
Mutation Taster		=73/27	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: rs574418224; hg19: chr11-396866;