rs3756323

Positions:

• chr5-141199785-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018931.3(PCDHB11):​c.11A>G​(p.Gln4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,578 control chromosomes in the GnomAD database, including 24,300 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2797 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21503 hom.)
• Consequence: PCDHB11 NM_018931.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.578

Genes affected

PCDHB11 (HGNC:8682): (protocadherin beta 11) 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]

PCDHB@ (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009645015).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB11	NM_018931.3	c.11A>G	p.Gln4Arg	missense_variant	1/1	ENST00000354757.5	NP_061754.1
PCDHB@		n.141199785A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB11	ENST00000354757.5	c.11A>G	p.Gln4Arg	missense_variant	1/1	6	NM_018931.3	ENSP00000346802.3
PCDHB11	ENST00000624887	c.-388A>G		5_prime_UTR_variant	1/2	2		ENSP00000485553.1
ENSG00000280029	ENST00000624192.1	n.72+41888T>C		intron_variant		5
ENSG00000278936	ENST00000624549.1	n.131+1481T>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27846 AN: 152096 Hom.: 2796 Cov.: 33

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.0472

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.155 AC: 38843 AN: 251174 Hom.: 3464 AF XY: 0.152 AC XY: 20607 AN XY: 135760

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.199

Gnomad EAS exome AF: 0.0347

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.166 AC: 243227 AN: 1461364 Hom.: 21503 Cov.: 31 AF XY: 0.164 AC XY: 119089 AN XY: 726986

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.200

Gnomad4 EAS exome AF: 0.0526

Gnomad4 SAS exome AF: 0.109

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.174

GnomAD4 genome AF: 0.183 AC: 27856 AN: 152214 Hom.: 2797 Cov.: 33 AF XY: 0.178 AC XY: 13268 AN XY: 74426

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.214

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.0473

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.192

Alfa AF: 0.172 Hom.: 5234

Bravo AF: 0.197

TwinsUK AF: 0.167 AC: 620

ALSPAC AF: 0.176 AC: 680

ESP6500AA AF: 0.237 AC: 1043

ESP6500EA AF: 0.171 AC: 1473

ExAC AF: 0.153 AC: 18608

Asia WGS AF: 0.0790 AC: 278 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.187

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.36
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.032
Sift	Benign	0.91	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.24
ClinPred		0.000011	T
GERP RS		0.24
Varity_R		0.020
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs3756323; hg19: chr5-140579358; COSMIC: COSV53377007; COSMIC: COSV53377007;