5-141178398-C-G

Position:

chr5-141178398-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019120.5(PCDHB8):c.364C>G(p.Leu122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000873 in 1,603,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PCDHB8
NM_019120.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16

Variant links:

Genes affected

PCDHB8 (HGNC:8693): (protocadherin beta 8) 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]

PCDHB8 links:

PCDHB@ (HGNC:8679):

PCDHB@ links:

ENSG00000279472 (HGNC:):

ENSG00000279472 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.093118995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB8	NM_019120.5 link	c.364C>G	p.Leu122Val	missense_variant	1/1	ENST00000239444.4	NP_061993.3	Q9UN66
PCDHB@		n.141178398C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PCDHB8	ENST00000239444.4 link	c.364C>G	p.Leu122Val	missense_variant	1/1	6	NM_019120.5	ENSP00000239444.2	Q9UN66
ENSG00000279472	ENST00000623995.1 link	n.221+329C>G		intron_variant		4
ENSG00000280029	ENST00000624192.1 link	n.73-41215G>C		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000533

AC:

AN:

150194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

247790

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134832

show subpopulations

Gnomad AFR exome

AF:

0.000272

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1453488

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723492

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000533

AC:

AN:

150194

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73186

show subpopulations

Gnomad4 AFR

AF:

0.000172

Gnomad4 AMR

AF:

0.0000663

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.000935

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

The c.364C>G (p.L122V) alteration is located in exon 1 (coding exon 1) of the PCDHB8 gene. This alteration results from a C to G substitution at nucleotide position 364, causing the leucine (L) at amino acid position 122 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.84

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.041

M_CAP

Benign

0.012

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.064

Sift

Benign

0.21

Sift4G

Benign

1.0

Vest4

0.16

MVP

0.27

MPC

0.27

ClinPred

0.14

GERP RS

2.2

gMVP

0.046

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