5-141956699-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016580.4(PCDH12):c.1153C>A(p.His385Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,613,964 control chromosomes in the GnomAD database, including 264,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 33951 hom., cov: 33)

Exomes 𝑓: 0.55 ( 231013 hom. )

Consequence

PCDH12
NM_016580.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.00200

Variant links:

Genes affected

PCDH12 (HGNC:8657): (protocadherin 12) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 6 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene localizes to the region on chromosome 5 where the protocadherin gene clusters reside. The exon organization of this transcript is similar to that of the gene cluster transcripts, notably the first large exon, but no significant sequence homology exists. The function of this cellular adhesion protein is undetermined but mouse protocadherin 12 does not bind catenins and appears to have no affect on cell migration or growth. [provided by RefSeq, Jul 2008]

PCDH12 links:

RNF14 (HGNC:10058): (ring finger protein 14) The protein encoded by this gene contains a RING zinc finger, a motif known to be involved in protein-protein interactions. This protein interacts with androgen receptor (AR) and may function as a coactivator that induces AR target gene expression in prostate. A dominant negative mutant of this gene has been demonstrated to inhibit the AR-mediated growth of prostate cancer. This protein also interacts with class III ubiquitin-conjugating enzymes (E2s) and may act as a ubiquitin-ligase (E3) in the ubiquitination of certain nuclear proteins. Six alternatively spliced transcript variants encoding two distinct isoforms have been reported. [provided by RefSeq, Jan 2011]

RNF14 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.851735E-5).

BP6

Variant 5-141956699-G-T is Benign according to our data. Variant chr5-141956699-G-T is described in ClinVar as [Benign]. Clinvar id is 512678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH12	NM_016580.4 link	c.1153C>A	p.His385Asn	missense_variant	Exon 1 of 4	ENST00000231484.4	NP_057664.1	Q9NPG4
RNF14	XM_047417904.1 link	c.-181+7289G>T		intron_variant	Intron 1 of 8		XP_047273860.1
RNF14	XM_047417908.1 link	c.-181+7289G>T		intron_variant	Intron 1 of 7		XP_047273864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH12	ENST00000231484.4 link	c.1153C>A	p.His385Asn	missense_variant	Exon 1 of 4	1	NM_016580.4	ENSP00000231484.3		Q9NPG4

Frequencies

GnomAD3 genomes

AF:

0.648

AC:

98498

AN:

152020

Hom.:

33890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.874

Gnomad AMI

AF:

0.344

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.519

Gnomad EAS

AF:

0.820

Gnomad SAS

AF:

0.739

Gnomad FIN

AF:

0.503

Gnomad MID

AF:

0.567

Gnomad NFE

AF:

0.520

Gnomad OTH

AF:

0.649

GnomAD3 exomes

AF:

0.621

AC:

156099

AN:

251292

Hom.:

50743

AF XY:

0.617

AC XY:

83750

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.875

Gnomad AMR exome

AF:

0.732

Gnomad ASJ exome

AF:

0.525

Gnomad EAS exome

AF:

0.815

Gnomad SAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.499

Gnomad NFE exome

AF:

0.522

Gnomad OTH exome

AF:

0.577

GnomAD4 exome

AF:

0.554

AC:

809370

AN:

1461826

Hom.:

231013

Cov.:

AF XY:

0.557

AC XY:

405254

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.881

Gnomad4 AMR exome

AF:

0.723

Gnomad4 ASJ exome

AF:

0.527

Gnomad4 EAS exome

AF:

0.842

Gnomad4 SAS exome

AF:

0.735

Gnomad4 FIN exome

AF:

0.501

Gnomad4 NFE exome

AF:

0.514

Gnomad4 OTH exome

AF:

0.576

GnomAD4 genome

AF:

0.648

AC:

98615

AN:

152138

Hom.:

33951

Cov.:

AF XY:

0.651

AC XY:

48372

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.874

Gnomad4 AMR

AF:

0.669

Gnomad4 ASJ

AF:

0.519

Gnomad4 EAS

AF:

0.820

Gnomad4 SAS

AF:

0.738

Gnomad4 FIN

AF:

0.503

Gnomad4 NFE

AF:

0.520

Gnomad4 OTH

AF:

0.646

Alfa

AF:

0.553

Hom.:

50228

Bravo

AF:

0.668

TwinsUK

AF:

0.508

AC:

1883

ALSPAC

AF:

0.511

AC:

1970

ESP6500AA

AF:

0.861

AC:

3793

ESP6500EA

AF:

0.516

AC:

4438

ExAC

AF:

0.628

AC:

76244

Asia WGS

AF:

0.727

AC:

2527

AN:

3478

EpiCase

AF:

0.528

EpiControl

AF:

0.525

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 22, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diencephalic-mesencephalic junction dysplasia syndrome 1

Benign:1

Sep 05, 2021

Genome-Nilou Lab

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

0.046

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.7

DANN

Benign

0.75

DEOGEN2

Benign

0.021

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.025

MetaRNN

Benign

0.000099

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.83

PrimateAI

Benign

0.40

PROVEAN

Benign

0.91

REVEL

Benign

0.069

Sift

Benign

0.49

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.019

MPC

0.20

ClinPred

0.0018

GERP RS

2.5

Varity_R

0.065

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over