chr5-141122761-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018938.4(PCDHB4):c.763C>T(p.Pro255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,613,220 control chromosomes in the GnomAD database, including 25,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P255L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.18 ( 2482 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22643 hom. )

Consequence

PCDHB4
NM_018938.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.705

Variant links:

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]

PCDHB4 links:

PCDHB@ (HGNC:8679):

PCDHB@ links:

ENSG00000272154 (HGNC:):

ENSG00000272154 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017100573).

BP6

Variant 5-141122761-C-T is Benign according to our data. Variant chr5-141122761-C-T is described in ClinVar as [Benign]. Clinvar id is 1242104.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 rank	MANE	Protein	UniProt
PCDHB4	NM_018938.4 link	c.763C>T	p.Pro255Ser	missense_variant	Exon 1 of 1	ENST00000194152.4	NP_061761.1	Q9Y5E5
PCDHB@		n.141122761C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHB4	ENST00000194152.4 link	c.763C>T	p.Pro255Ser	missense_variant	Exon 1 of 1	6	NM_018938.4	ENSP00000194152.1		Q9Y5E5

Frequencies

GnomAD3 genomes

AF:

0.177

AC:

26879

AN:

151932

Hom.:

2481

Cov.:

show subpopulations

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:

0.122

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:

41212

AN:

251376

Hom.:

3629

AF XY:

0.162

AC XY:

21995

AN XY:

135862

show subpopulations

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:

251581

AN:

1461172

Hom.:

22643

Cov.:

AF XY:

0.171

AC XY:

123963

AN XY:

726926

show subpopulations

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:

26885

AN:

152048

Hom.:

2482

Cov.:

AF XY:

0.174

AC XY:

12925

AN XY:

74352

show subpopulations

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:

0.177

Hom.:

4395

Bravo

AF:

0.188

TwinsUK

AF:

0.171

AC:

635

ALSPAC

AF:

0.184

AC:

708

ESP6500AA

AF:

0.193

AC:

852

ESP6500EA

AF:

0.168

AC:

1448

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

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.045

Eigen

Benign

0.057

Eigen_PC

Benign

0.024

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.32

PROVEAN

Pathogenic

-5.9

REVEL

Benign

0.15

Sift

Benign

0.058

Sift4G

Benign

0.079

Polyphen

0.46

Vest4

0.14

ClinPred

0.051

GERP RS

3.5

Varity_R

0.22

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over