rs3822357

Positions:

• chr5-141864791-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032420.5(PCDH1):​c.1540G>A​(p.Ala514Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.072 in 1,614,012 control chromosomes in the GnomAD database, including 4,887 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.068 (465 hom., cov: 32)
  • Exomes 𝑓: 0.072 (4422 hom.)
• Consequence: PCDH1 NM_032420.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

Genes affected

PCDH1 (HGNC:8655): (protocadherin 1) This gene belongs to the protocadherin subfamily within the cadherin superfamily. The encoded protein is a membrane protein found at cell-cell boundaries. It is involved in neural cell adhesion, suggesting a possible role in neuronal development. The protein includes an extracelllular region, containing 7 cadherin-like domains, a transmembrane region and a C-terminal cytoplasmic region. Cells expressing the protein showed cell aggregation activity. Alternative splicing occurs in this gene. [provided by RefSeq, Jul 2008]

PCDH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001683265).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5	c.1540G>A	p.Ala514Thr	missense_variant	3/5	ENST00000287008.8	NP_115796.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH1	ENST00000287008.8	c.1540G>A	p.Ala514Thr	missense_variant	3/5	5	NM_032420.5	ENSP00000287008.3

Frequencies

GnomAD3 genomes AF: 0.0682 AC: 10373 AN: 152018 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0907

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0685

GnomAD3 exomes AF: 0.0913 AC: 22940 AN: 251328 Hom.: 1339 AF XY: 0.0903 AC XY: 12267 AN XY: 135836

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.0458

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0642

Gnomad OTH exome AF: 0.0847

GnomAD4 exome AF: 0.0724 AC: 105888 AN: 1461874 Hom.: 4422 Cov.: 36 AF XY: 0.0733 AC XY: 53317 AN XY: 727240

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.0436

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0634

Gnomad4 OTH exome AF: 0.0736

GnomAD4 genome AF: 0.0683 AC: 10391 AN: 152138 Hom.: 465 Cov.: 32 AF XY: 0.0723 AC XY: 5374 AN XY: 74376

Gnomad4 AFR AF: 0.0357

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.0427

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.0907

Gnomad4 NFE AF: 0.0637

Gnomad4 OTH AF: 0.0692

Alfa AF: 0.0666 Hom.: 979

Bravo AF: 0.0695

TwinsUK AF: 0.0645 AC: 239

ALSPAC AF: 0.0610 AC: 235

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.0606 AC: 521

ExAC AF: 0.0866 AC: 10519

Asia WGS AF: 0.121 AC: 420 AN: 3478

EpiCase AF: 0.0625

EpiControl AF: 0.0608

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.40	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.59	N;N
REVEL	Benign	0.084
Sift	Benign	0.14	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.94	P;P
Vest4		0.022
MPC		0.45
ClinPred		0.011	T
GERP RS		3.9
Varity_R		0.058
gMVP		0.097

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

Publications

LitVar

Other links and lift over

dbSNP: rs3822357; hg19: chr5-141244356; COSMIC: COSV54617845; COSMIC: COSV54617845;