5-141199785-A-G

Variant names:

• chr5-141199785-A-G
• rs3756323
• NM_018931.3:c.11A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 20 publications found

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:8679):

ENSG00000280029 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018931.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB11	NM_018931.3	MANE Select	c.11A>G	p.Gln4Arg	missense	Exon 1 of 1	NP_061754.1	Q9Y5F2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB11	ENST00000354757.5	TSL:6 MANE Select	c.11A>G	p.Gln4Arg	missense	Exon 1 of 1	ENSP00000346802.3	Q9Y5F2-1
	PCDHB11	ENST00000624887.1	TSL:2	c.-388A>G		5_prime_UTR	Exon 1 of 2	ENSP00000485553.1	Q9Y5F2-2
	ENSG00000280029	ENST00000624192.1	TSL:5	n.72+41888T>C		intron	N/A

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

GnomAD2 exomes AF: 0.155 AC: 38843 AN: 251174 AF XY: 0.152

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 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

African (AFR) AF: 0.245 AC: 8195 AN: 33446

American (AMR) AF: 0.189 AC: 8461 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5233 AN: 26114

East Asian (EAS) AF: 0.0526 AC: 2089 AN: 39698

South Asian (SAS) AF: 0.109 AC: 9358 AN: 86246

European-Finnish (FIN) AF: 0.101 AC: 5392 AN: 53414

Middle Eastern (MID) AF: 0.201 AC: 1160 AN: 5768

European-Non Finnish (NFE) AF: 0.173 AC: 192840 AN: 1111612

Other (OTH) AF: 0.174 AC: 10499 AN: 60364

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

African (AFR) AF: 0.242 AC: 10030 AN: 41502

American (AMR) AF: 0.214 AC: 3276 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 616 AN: 3470

East Asian (EAS) AF: 0.0473 AC: 245 AN: 5182

South Asian (SAS) AF: 0.109 AC: 526 AN: 4826

European-Finnish (FIN) AF: 0.107 AC: 1137 AN: 10618

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11355 AN: 68008

Other (OTH) AF: 0.192 AC: 405 AN: 2112

Alfa AF: 0.176 Hom.: 7859

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 v4.9

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
PhyloP100		-0.58
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
PromoterAI		0.046	Neutral
Varity_R		0.020
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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