5-141122762-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018938.4(PCDHB4):c.764C>T(p.Pro255Leu) variant causes a missense change. The variant allele was found at a frequency of 0.173 in 1,613,194 control chromosomes in the GnomAD database, including 25,127 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P255S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.18 (2483 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22644 hom.)
• Consequence: PCDHB4 NM_018938.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.00

Genes affected

PCDHB4 (HGNC:8689): (protocadherin beta 4) This gene is a member of the protocadherin beta gene cluster, one of three related gene clusters tandemly linked on chromosome five. The gene clusters demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The beta cluster contains 16 genes and 3 pseudogenes, each encoding 6 extracellular cadherin domains and a cytoplasmic tail that deviates from others in the cadherin superfamily. The extracellular domains interact in a homophilic manner to specify differential cell-cell connections. Unlike the alpha and gamma clusters, the transcripts from these genes are made up of only one large exon, not sharing common 3' exons as expected. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins. Their specific functions are unknown but they most likely play a critical role in the establishment and function of specific cell-cell neural connections. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017229617).
• BP6: Variant 5-141122762-C-T is Benign according to our data. Variant chr5-141122762-C-T is described in ClinVar as [Benign]. Clinvar id is 1223922.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB4	NM_018938.4	c.764C>T	p.Pro255Leu	missense_variant	1/1	ENST00000194152.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHB4	ENST00000194152.4	c.764C>T	p.Pro255Leu	missense_variant	1/1		NM_018938.4	P1
	ENST00000624802.1	n.365-22007G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26884 AN: 151904 Hom.: 2482 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.164 AC: 41211 AN: 251378 Hom.: 3629 AF XY: 0.162 AC XY: 21993 AN XY: 135862

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.112

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.172 AC: 251579 AN: 1461174 Hom.: 22644 Cov.: 36 AF XY: 0.171 AC XY: 123957 AN XY: 726914

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.177 AC: 26890 AN: 152020 Hom.: 2483 Cov.: 32 AF XY: 0.174 AC XY: 12930 AN XY: 74322

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.186

Alfa AF: 0.178 Hom.: 5431

Bravo AF: 0.188

TwinsUK AF: 0.171 AC: 635

ALSPAC AF: 0.184 AC: 709

ESP6500AA AF: 0.194 AC: 853

ESP6500EA AF: 0.168 AC: 1444

ExAC AF: 0.162 AC: 19622

Asia WGS AF: 0.120 AC: 418 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.195

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	0.089
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	3.4e-7	P
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Benign	0.18
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.16	B
Vest4		0.42
ClinPred		0.091	T
GERP RS		4.4
Varity_R		0.49
gMVP		0.22

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: rs3733697; hg19: chr5-140502344; COSMIC: COSV52020879; COSMIC: COSV52020879;