chr5-141122595-G-A

Variant names:

• chr5-141122595-G-A
• rs3776100
• NM_018938.4:c.597G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_018938.4(PCDHB4):​c.597G>A​(p.Leu199Leu) 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
• Publications: 27 publications found

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]

PCDHB@ (HGNC:8679):

ENSG00000272154 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018938.4. 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
	PCDHB4	NM_018938.4	MANE Select	c.597G>A	p.Leu199Leu	synonymous	Exon 1 of 1	NP_061761.1	Q9Y5E5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDHB4	ENST00000194152.4	TSL:6 MANE Select	c.597G>A	p.Leu199Leu	synonymous	Exon 1 of 1	ENSP00000194152.1	Q9Y5E5
	PCDHB4	ENST00000623478.1	TSL:1	n.214-560G>A		intron	N/A
	ENSG00000272154	ENST00000624802.1	TSL:3	n.365-21840C>T		intron	N/A

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

GnomAD2 exomes AF: 0.259 AC: 65212 AN: 251402 AF XY: 0.262

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 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

African (AFR) AF: 0.0414 AC: 1385 AN: 33480

American (AMR) AF: 0.332 AC: 14857 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6909 AN: 26136

East Asian (EAS) AF: 0.455 AC: 18063 AN: 39700

South Asian (SAS) AF: 0.333 AC: 28759 AN: 86250

European-Finnish (FIN) AF: 0.191 AC: 10188 AN: 53414

Middle Eastern (MID) AF: 0.192 AC: 1110 AN: 5768

European-Non Finnish (NFE) AF: 0.229 AC: 254630 AN: 1111990

Other (OTH) AF: 0.232 AC: 14032 AN: 60396

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

African (AFR) AF: 0.0464 AC: 1929 AN: 41564

American (AMR) AF: 0.267 AC: 4091 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 975 AN: 3470

East Asian (EAS) AF: 0.434 AC: 2230 AN: 5140

South Asian (SAS) AF: 0.316 AC: 1523 AN: 4820

European-Finnish (FIN) AF: 0.177 AC: 1879 AN: 10594

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15664 AN: 67986

Other (OTH) AF: 0.200 AC: 422 AN: 2108

Alfa AF: 0.221 Hom.: 5602

Bravo AF: 0.192

Asia WGS AF: 0.310 AC: 1080 AN: 3478

EpiCase AF: 0.229

EpiControl AF: 0.230

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.5
DANN	Benign	0.59
PhyloP100		0.021
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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