Variant chr5-141122904-GA-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018938.4(PCDHB4):c.915delA(p.Lys305AsnfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000079 in 1,594,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

PCDHB4
NM_018938.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 0.644

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB4	NM_018938.4 link	c.915delA	p.Lys305AsnfsTer12	frameshift_variant	Exon 1 of 1	ENST00000194152.4	NP_061761.1	Q9Y5E5
PCDHB@		n.141122913delA		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHB4	ENST00000194152.4 link	c.915delA	p.Lys305AsnfsTer12	frameshift_variant	Exon 1 of 1	6	NM_018938.4	ENSP00000194152.1		Q9Y5E5

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

151038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000462

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000686

AC:

AN:

1443474

Hom.:

Cov.:

AF XY:

0.0000696

AC XY:

AN XY:

717982

show subpopulations

Gnomad4 AFR exome

AF:

0.000247

Gnomad4 AMR exome

AF:

0.000145

Gnomad4 ASJ exome

AF:

0.0000783

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000719

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000608

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.000179

AC:

AN:

151156

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

73848

show subpopulations

Gnomad4 AFR

AF:

0.000461

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.000210

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000443

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000249

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Seizure;C3714756:Intellectual disability;C4551563:Microcephaly

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Dec 01, 2014

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Sep 23, 2020

- -

Epilepsy;C3714756:Intellectual disability;C4551563:Microcephaly

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

Variant interpreted as Uncertain significance and reported on 09-23-2020 by Lab or GTR ID New York Genome Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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