5-141122595-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_018938.4(PCDHB4):c.597G>A(p.Leu199=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,614,036 control chromosomes in the GnomAD database, including 48,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3631 hom., cov: 33)
  • Exomes 𝑓: 0.24 (44731 hom.)
• Consequence: PCDHB4 NM_018938.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0210

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-141122595-G-A is Benign according to our data. Variant chr5-141122595-G-A is described in ClinVar as [Benign]. Clinvar id is 1182422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.021 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDHB4	NM_018938.4	c.597G>A	p.Leu199=	synonymous_variant	1/1	ENST00000194152.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDHB4	ENST00000194152.4	c.597G>A	p.Leu199=	synonymous_variant	1/1		NM_018938.4	P1
	ENST00000624802.1	n.365-21840C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.191 AC: 28976 AN: 152064 Hom.: 3632 Cov.: 33

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.259 AC: 65212 AN: 251402 Hom.: 9467 AF XY: 0.262 AC XY: 35586 AN XY: 135868

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.267

Gnomad EAS exome AF: 0.435

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.239 AC: 349933 AN: 1461852 Hom.: 44731 Cov.: 36 AF XY: 0.243 AC XY: 176526 AN XY: 727220

Gnomad4 AFR exome AF: 0.0414

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.190 AC: 28978 AN: 152184 Hom.: 3631 Cov.: 33 AF XY: 0.193 AC XY: 14382 AN XY: 74404

Gnomad4 AFR AF: 0.0464

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.281

Gnomad4 EAS AF: 0.434

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.200

Alfa AF: 0.228 Hom.: 4563

Bravo AF: 0.192

Asia WGS AF: 0.310 AC: 1080 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.230

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

GeneDx

Oct 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	7.5
Dann	Benign	0.59

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: rs3776100; hg19: chr5-140502177; COSMIC: COSV52019652; COSMIC: COSV52019652;