NM_018938.4:c.763C>T

Variant names:

• chr5-141122761-C-T
• rs3733698
• NM_018938.4:c.763C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018938.4(PCDHB4):​c.763C>T​(p.Pro255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,613,220 control chromosomes in the GnomAD database, including 25,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P255L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.18 (2482 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22643 hom.)
• Consequence: PCDHB4 NM_018938.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.705
• Publications: 21 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017100573).
• BP6: Variant 5-141122761-C-T is Benign according to our data. Variant chr5-141122761-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 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.763C>T	p.Pro255Ser	missense	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.763C>T	p.Pro255Ser	missense	Exon 1 of 1	ENSP00000194152.1	Q9Y5E5
	PCDHB4	ENST00000623478.1	TSL:1	n.214-394C>T		intron	N/A
	ENSG00000272154	ENST00000624802.1	TSL:3	n.365-22006G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26879 AN: 151932 Hom.: 2481 Cov.: 32

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.306

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.164 AC: 41212 AN: 251376 AF XY: 0.162

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.172 AC: 251581 AN: 1461172 Hom.: 22643 Cov.: 36 AF XY: 0.171 AC XY: 123963 AN XY: 726926

African (AFR) AF: 0.207 AC: 6919 AN: 33464

American (AMR) AF: 0.189 AC: 8453 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5539 AN: 26132

East Asian (EAS) AF: 0.116 AC: 4592 AN: 39698

South Asian (SAS) AF: 0.111 AC: 9596 AN: 86236

European-Finnish (FIN) AF: 0.110 AC: 5893 AN: 53410

Middle Eastern (MID) AF: 0.221 AC: 1277 AN: 5768

European-Non Finnish (NFE) AF: 0.178 AC: 198352 AN: 1111372

Other (OTH) AF: 0.182 AC: 10960 AN: 60374

GnomAD4 genome AF: 0.177 AC: 26885 AN: 152048 Hom.: 2482 Cov.: 32 AF XY: 0.174 AC XY: 12925 AN XY: 74352

African (AFR) AF: 0.195 AC: 8072 AN: 41466

American (AMR) AF: 0.218 AC: 3327 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3468

East Asian (EAS) AF: 0.129 AC: 666 AN: 5160

South Asian (SAS) AF: 0.122 AC: 588 AN: 4812

European-Finnish (FIN) AF: 0.116 AC: 1227 AN: 10592

Middle Eastern (MID) AF: 0.315 AC: 92 AN: 292

European-Non Finnish (NFE) AF: 0.172 AC: 11702 AN: 67952

Other (OTH) AF: 0.186 AC: 391 AN: 2106

Alfa AF: 0.176 Hom.: 8479

Bravo AF: 0.188

TwinsUK AF: 0.171 AC: 635

ALSPAC AF: 0.184 AC: 708

ESP6500AA AF: 0.193 AC: 852

ESP6500EA AF: 0.168 AC: 1448

ExAC AF: 0.162 AC: 19622

Asia WGS AF: 0.120 AC: 418 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.195

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T
Eigen	Benign	0.057
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.70
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.15
Sift	Benign	0.058	T
Sift4G	Benign	0.079	T
Polyphen		0.46	P
Vest4		0.14
ClinPred		0.051	T
GERP RS		3.5
Varity_R		0.22
gMVP		0.20
Mutation Taster		=94/6	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: rs3733698; hg19: chr5-140502343; COSMIC: COSV52020869; COSMIC: COSV52020869;