11-396686-C-G

Variant names:

• chr11-396686-C-G
• rs149396982
• NM_007183.4:c.311C>G
• PKP3 p.Ser104Trp

Variant summary

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

The NM_007183.4(PKP3):​c.311C>G​(p.Ser104Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S104L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PKP3 NM_007183.4 missense, splice_region
• Scores: Splicing: ADA: 0.006367
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0940
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2846787).

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.311C>G	p.Ser104Trp	missense splice_region	Exon 2 of 13	NP_009114.1	Q9Y446-1
	PKP3	NM_001303029.2		c.356C>G	p.Ser119Trp	missense splice_region	Exon 3 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.311C>G	p.Ser104Trp	missense splice_region	Exon 2 of 13	ENSP00000331678.2	Q9Y446-1
	PKP3	ENST00000527442.6	TSL:3	c.-158C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	ENSP00000435522.2	E9PRW6
	PKP3	ENST00000528036.6	TSL:2	c.-158C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	ENSP00000434110.2	E9PRW6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457386 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724838

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110154

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.094
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.099
gMVP		0.54
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0064
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs149396982;

hg19: chr11-396686;