dbSNP rs3776096: PCDHB6:p.Val231Ile (chr5-141150948-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018939.4(PCDHB6):c.691G>A(p.Val231Ile) variant causes a missense change. The variant allele was found at a frequency of 0.239 in 1,613,852 control chromosomes in the GnomAD database, including 51,001 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.20 ( 3830 hom., cov: 32)

Exomes 𝑓: 0.24 ( 47171 hom. )

Consequence

PCDHB6
NM_018939.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.03

Variant links:

Genes affected

PCDHB6 (HGNC:8691): (protocadherin beta 6) 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. Unlike the alpha and gamma clusters, the transcripts from these genes do not share common 3' exons. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell neural connections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PCDHB6 links:

PCDHB@ (HGNC:8679):

PCDHB@ links:

ENSG00000280029 (HGNC:):

ENSG00000280029 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014867485).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB6	NM_018939.4 link	c.691G>A	p.Val231Ile	missense_variant	Exon 1 of 1	ENST00000231136.4	NP_061762.2	Q9Y5E3
PCDHB6	NM_001303145.2 link	c.283G>A	p.Val95Ile	missense_variant	Exon 2 of 2		NP_001290074.1	Q9Y5E3B4DSB6A0A096LNH7
PCDHB@		n.141150948G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHB6	ENST00000231136.4 link	c.691G>A	p.Val231Ile	missense_variant	Exon 1 of 1	6	NM_018939.4	ENSP00000231136.1		Q9Y5E3

Frequencies

GnomAD3 genomes

AF:

0.195

AC:

29684

AN:

151910

Hom.:

3831

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0463

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.264

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.503

Gnomad SAS

AF:

0.324

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.210

GnomAD3 exomes

AF:

0.270

AC:

67779

AN:

251238

Hom.:

10445

AF XY:

0.272

AC XY:

36942

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.237

Gnomad EAS exome

AF:

0.503

Gnomad SAS exome

AF:

0.338

Gnomad FIN exome

AF:

0.216

Gnomad NFE exome

AF:

0.235

Gnomad OTH exome

AF:

0.245

GnomAD4 exome

AF:

0.244

AC:

356658

AN:

1461822

Hom.:

47171

Cov.:

AF XY:

0.248

AC XY:

180069

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0390

Gnomad4 AMR exome

AF:

0.343

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.536

Gnomad4 SAS exome

AF:

0.340

Gnomad4 FIN exome

AF:

0.216

Gnomad4 NFE exome

AF:

0.231

Gnomad4 OTH exome

AF:

0.232

GnomAD4 genome

AF:

0.195

AC:

29688

AN:

152030

Hom.:

3830

Cov.:

AF XY:

0.199

AC XY:

14766

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0462

Gnomad4 AMR

AF:

0.264

Gnomad4 ASJ

AF:

0.248

Gnomad4 EAS

AF:

0.503

Gnomad4 SAS

AF:

0.325

Gnomad4 FIN

AF:

0.206

Gnomad4 NFE

AF:

0.234

Gnomad4 OTH

AF:

0.212

Alfa

AF:

0.236

Hom.:

9788

Bravo

AF:

0.194

TwinsUK

AF:

0.244

AC:

906

ALSPAC

AF:

0.229

AC:

884

ESP6500AA

AF:

0.0429

AC:

189

ESP6500EA

AF:

0.231

AC:

1988

ExAC

AF:

0.265

AC:

32162

Asia WGS

AF:

0.335

AC:

1165

AN:

3478

EpiCase

AF:

0.227

EpiControl

AF:

0.233

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

.;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.63

.;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.79

N;.

REVEL

Benign

0.045

Sift

Benign

0.17

T;.

Sift4G

Benign

0.14

T;T

Vest4

0.086

ClinPred

0.026

GERP RS

3.1

gMVP

0.14

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over