Genetic Variant PCDHB4:p.Leu199Leu (chr5-141122595-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_018938.4(PCDHB4):c.597G>A(p.Leu199Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,614,036 control chromosomes in the GnomAD database, including 48,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.19 ( 3631 hom., cov: 33)

Exomes 𝑓: 0.24 ( 44731 hom. )

Consequence

PCDHB4
NM_018938.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0210

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 5-141122595-G-A is Benign according to our data. Variant chr5-141122595-G-A is described in ClinVar as [Benign]. Clinvar id is 1182422.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.021 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB4	NM_018938.4 link	c.597G>A	p.Leu199Leu	synonymous_variant	Exon 1 of 1	ENST00000194152.4	NP_061761.1	Q9Y5E5
PCDHB@		n.141122595G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHB4	ENST00000194152.4 link	c.597G>A	p.Leu199Leu	synonymous_variant	Exon 1 of 1	6	NM_018938.4	ENSP00000194152.1		Q9Y5E5

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28976

AN:

152064

Hom.:

3632

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0465

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.434

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.177

Gnomad MID

AF:

0.204

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.259

AC:

65212

AN:

251402

Hom.:

9467

AF XY:

0.262

AC XY:

35586

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0433

Gnomad AMR exome

AF:

0.342

Gnomad ASJ exome

AF:

0.267

Gnomad EAS exome

AF:

0.435

Gnomad SAS exome

AF:

0.333

Gnomad FIN exome

AF:

0.189

Gnomad NFE exome

AF:

0.230

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.239

AC:

349933

AN:

1461852

Hom.:

44731

Cov.:

AF XY:

0.243

AC XY:

176526

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0414

Gnomad4 AMR exome

AF:

0.332

Gnomad4 ASJ exome

AF:

0.264

Gnomad4 EAS exome

AF:

0.455

Gnomad4 SAS exome

AF:

0.333

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.229

Gnomad4 OTH exome

AF:

0.232

GnomAD4 genome

AF:

0.190

AC:

28978

AN:

152184

Hom.:

3631

Cov.:

AF XY:

0.193

AC XY:

14382

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0464

Gnomad4 AMR

AF:

0.267

Gnomad4 ASJ

AF:

0.281

Gnomad4 EAS

AF:

0.434

Gnomad4 SAS

AF:

0.316

Gnomad4 FIN

AF:

0.177

Gnomad4 NFE

AF:

0.230

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.228

Hom.:

4563

Bravo

AF:

0.192

Asia WGS

AF:

0.310

AC:

1080

AN:

3478

EpiCase

AF:

0.229

EpiControl

AF:

0.230

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.5

DANN

Benign

0.59

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