chr5-141200001-A-G

Position:

• chr5-141200001-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018931.3(PCDHB11):​c.227A>G​(p.Gln76Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,614,194 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: PCDHB11 NM_018931.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0520

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016922414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHB11	NM_018931.3	c.227A>G	p.Gln76Arg	missense_variant	1/1	ENST00000354757.5	NP_061754.1
PCDHB@		n.141200001A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHB11	ENST00000354757.5	c.227A>G	p.Gln76Arg	missense_variant	1/1	6	NM_018931.3	ENSP00000346802.3
PCDHB11	ENST00000624887.1	c.-364+192A>G		intron_variant		2		ENSP00000485553.1
ENSG00000280029	ENST00000624192.1	n.72+41672T>C		intron_variant		5
ENSG00000278936	ENST00000624549.1	n.131+1265T>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.000662

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000465 AC: 117 AN: 251484 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135920

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000454 AC: 664 AN: 1461892 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 313 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000538

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74474

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.227A>G (p.Q76R) alteration is located in exon 1 (coding exon 1) of the PCDHB11 gene. This alteration results from a A to G substitution at nucleotide position 227, causing the glutamine (Q) at amino acid position 76 to be replaced by an arginine (R). 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	0.082
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.019
Sift	Benign	0.32	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.041
MVP		0.20
MPC		0.25
ClinPred		0.020	T
GERP RS		-1.4
Varity_R		0.043
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

Other links and lift over

dbSNP: rs141724856; hg19: chr5-140579574;