5-141122501-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018938.4(PCDHB4):c.503A>G(p.Lys168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,614,230 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (76 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (73 hom.)
• Consequence: PCDHB4 NM_018938.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.34

Genes affected

PCDHB4 (HGNC:8689): (protocadherin beta 4) 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026776195).
• BP6: Variant 5-141122501-A-G is Benign according to our data. Variant chr5-141122501-A-G is described in ClinVar as [Benign]. Clinvar id is 780568.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB4	NM_018938.4	c.503A>G	p.Lys168Arg	missense_variant	1/1	ENST00000194152.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHB4	ENST00000194152.4	c.503A>G	p.Lys168Arg	missense_variant	1/1		NM_018938.4	P1
	ENST00000624802.1	n.365-21746T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2675 AN: 152226 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00619 AC: 1556 AN: 251448 Hom.: 36 AF XY: 0.00455 AC XY: 618 AN XY: 135912

Gnomad AFR exome AF: 0.0642

Gnomad AMR exome AF: 0.00974

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.00227 AC: 3325 AN: 1461886 Hom.: 73 Cov.: 31 AF XY: 0.00199 AC XY: 1445 AN XY: 727240

Gnomad4 AFR exome AF: 0.0597

Gnomad4 AMR exome AF: 0.00970

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000451

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.0176 AC: 2681 AN: 152344 Hom.: 76 Cov.: 32 AF XY: 0.0168 AC XY: 1250 AN XY: 74494

Gnomad4 AFR AF: 0.0587

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00362 Hom.: 19

Bravo AF: 0.0203

ESP6500AA AF: 0.0617 AC: 272

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00717 AC: 871

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.00079	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.080	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.11	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.043
Sift	Uncertain	0.024	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.33
ClinPred		0.0026	T
GERP RS		2.0
Varity_R		0.082
gMVP		0.078

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: rs34350292; hg19: chr5-140502083;