5-141122177-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_018938.4(PCDHB4):c.179C>T(p.Ser60Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,614,172 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0047 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 2 hom. )

Consequence

PCDHB4
NM_018938.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.832

Publications

3 publications found

Variant links:

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]

PCDHB4 links:

PCDHB@ (HGNC:8679):

PCDHB@ links:

ENSG00000272154 (HGNC:):

ENSG00000272154 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009034723).

BP6

Variant 5-141122177-C-T is Benign according to our data. Variant chr5-141122177-C-T is described in ClinVar as [Benign]. Clinvar id is 776068.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00472 (719/152290) while in subpopulation AFR AF = 0.0162 (675/41566). AF 95% confidence interval is 0.0152. There are 14 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHB4	NM_018938.4 link	c.179C>T	p.Ser60Phe	missense_variant	Exon 1 of 1	ENST00000194152.4	NP_061761.1	Q9Y5E5
PCDHB@		n.141122177C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHB4	ENST00000194152.4 link	c.179C>T	p.Ser60Phe	missense_variant	Exon 1 of 1	6	NM_018938.4	ENSP00000194152.1		Q9Y5E5

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

707

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

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:

0.0000294

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00114

AC:

287

AN:

251392

AF XY:

0.000890

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000436

AC:

638

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000358

AC XY:

260

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0141

AC:

471

AN:

33480

American (AMR)

AF:

0.00107

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000369

AC:

AN:

1112010

Other (OTH)

AF:

0.00109

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00472

AC:

719

AN:

152290

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

341

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0162

AC:

675

AN:

41566

American (AMR)

AF:

0.00229

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00165

Hom.:

Bravo

AF:

0.00517

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00133

AC:

162

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.025

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.068

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

-0.83

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.11

Sift

Uncertain

0.011

Sift4G

Uncertain

0.028

Polyphen

0.027

Vest4

0.17

MVP

0.30

ClinPred

0.012

GERP RS

2.7

PromoterAI

0.097

Neutral

(source)

Varity_R

0.16

gMVP

0.44

Mutation Taster

=97/3

polymorphism

(source)

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

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5-141122177-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over