chr2-158533250-C-T

Variant names:

• chr2-158533250-C-T
• rs35112233
• NM_003628.6:c.66C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003628.6(PKP4):​c.66C>T​(p.Ala22Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0571 in 1,613,912 control chromosomes in the GnomAD database, including 3,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A22A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.053 (288 hom., cov: 32)
  • Exomes 𝑓: 0.058 (2831 hom.)
• Consequence: PKP4 NM_003628.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.60
• Publications: 5 publications found

Genes affected

PKP4 (HGNC:9026): (plakophilin 4) Armadillo-like proteins are characterized by a series of armadillo repeats, first defined in the Drosophila 'armadillo' gene product, that are typically 42 to 45 amino acids in length. These proteins can be divided into subfamilies based on their number of repeats, their overall sequence similarity, and the dispersion of the repeats throughout their sequences. Members of the p120(ctn)/plakophilin subfamily of Armadillo-like proteins, including CTNND1, CTNND2, PKP1, PKP2, PKP4, and ARVCF. PKP4 may be a component of desmosomal plaque and other adhesion plaques and is thought to be involved in regulating junctional plaque organization and cadherin function. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-158533250-C-T is Benign according to our data. Variant chr2-158533250-C-T is described in ClinVar as Benign. ClinVar VariationId is 1230040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003628.6. 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
	PKP4	NM_003628.6	MANE Select	c.66C>T	p.Ala22Ala	synonymous	Exon 2 of 22	NP_003619.2	Q99569-1
	PKP4	NM_001377218.1		c.66C>T	p.Ala22Ala	synonymous	Exon 2 of 22	NP_001364147.1	Q99569-1
	PKP4	NM_001304969.3		c.66C>T	p.Ala22Ala	synonymous	Exon 2 of 22	NP_001291898.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP4	ENST00000389759.8	TSL:1 MANE Select	c.66C>T	p.Ala22Ala	synonymous	Exon 2 of 22	ENSP00000374409.3	Q99569-1
	PKP4	ENST00000389757.7	TSL:1	c.66C>T	p.Ala22Ala	synonymous	Exon 2 of 21	ENSP00000374407.3	Q99569-2
	PKP4	ENST00000426248.7	TSL:1	n.66C>T		non_coding_transcript_exon	Exon 2 of 22	ENSP00000396827.2	E7EST6

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 8008 AN: 152104 Hom.: 289 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0662

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0527 AC: 13227 AN: 251068 AF XY: 0.0521

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0415

Gnomad ASJ exome AF: 0.0404

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0662

Gnomad OTH exome AF: 0.0666

GnomAD4 exome AF: 0.0575 AC: 84119 AN: 1461690 Hom.: 2831 Cov.: 31 AF XY: 0.0571 AC XY: 41522 AN XY: 727132

African (AFR) AF: 0.0150 AC: 501 AN: 33478

American (AMR) AF: 0.0427 AC: 1908 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 1035 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0188 AC: 1622 AN: 86240

European-Finnish (FIN) AF: 0.114 AC: 6086 AN: 53404

Middle Eastern (MID) AF: 0.0774 AC: 444 AN: 5734

European-Non Finnish (NFE) AF: 0.0624 AC: 69358 AN: 1111912

Other (OTH) AF: 0.0524 AC: 3163 AN: 60386

GnomAD4 genome AF: 0.0526 AC: 8011 AN: 152222 Hom.: 288 Cov.: 32 AF XY: 0.0543 AC XY: 4041 AN XY: 74442

African (AFR) AF: 0.0186 AC: 774 AN: 41538

American (AMR) AF: 0.0630 AC: 963 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0172 AC: 83 AN: 4820

European-Finnish (FIN) AF: 0.122 AC: 1290 AN: 10596

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0662 AC: 4504 AN: 68004

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0521 Hom.: 230

Bravo AF: 0.0454

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0662

EpiControl AF: 0.0639

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		3.6
PromoterAI		-0.0024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs35112233; hg19: chr2-159389762; COSMIC: COSV67679722;