5-141956699-G-T

Variant names:

• chr5-141956699-G-T
• rs164075
• NM_016580.4:c.1153C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 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. H385Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.65 (33951 hom., cov: 33)
  • Exomes 𝑓: 0.55 (231013 hom.)
• Consequence: PCDH12 NM_016580.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00200
• Publications: 41 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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	c.1153C>A	p.His385Asn	missense_variant	Exon 1 of 4	ENST00000231484.4	NP_057664.1
RNF14	XM_047417904.1	c.-181+7289G>T		intron_variant	Intron 1 of 8		XP_047273860.1
RNF14	XM_047417908.1	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	c.1153C>A	p.His385Asn	missense_variant	Exon 1 of 4	1	NM_016580.4	ENSP00000231484.3

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98498 AN: 152020 Hom.: 33890 Cov.: 33

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

GnomAD2 exomes AF: 0.621 AC: 156099 AN: 251292 AF XY: 0.617

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 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.: 68 AF XY: 0.557 AC XY: 405254 AN XY: 727220

African (AFR) AF: 0.881 AC: 29504 AN: 33480

American (AMR) AF: 0.723 AC: 32341 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 13771 AN: 26136

East Asian (EAS) AF: 0.842 AC: 33410 AN: 39698

South Asian (SAS) AF: 0.735 AC: 63418 AN: 86256

European-Finnish (FIN) AF: 0.501 AC: 26785 AN: 53418

Middle Eastern (MID) AF: 0.623 AC: 3593 AN: 5768

European-Non Finnish (NFE) AF: 0.514 AC: 571767 AN: 1111950

Other (OTH) AF: 0.576 AC: 34781 AN: 60396

GnomAD4 genome AF: 0.648 AC: 98615 AN: 152138 Hom.: 33951 Cov.: 33 AF XY: 0.651 AC XY: 48372 AN XY: 74356

African (AFR) AF: 0.874 AC: 36301 AN: 41518

American (AMR) AF: 0.669 AC: 10235 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 1801 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4241 AN: 5174

South Asian (SAS) AF: 0.738 AC: 3557 AN: 4818

European-Finnish (FIN) AF: 0.503 AC: 5318 AN: 10576

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.520 AC: 35318 AN: 67972

Other (OTH) AF: 0.646 AC: 1366 AN: 2114

Alfa AF: 0.569 Hom.: 71436

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

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	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.7
DANN	Benign	0.75
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.025	T
MetaRNN	Benign	0.000099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N
PhyloP100		0.0020
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.069
Sift	Benign	0.49	T
Sift4G	Benign	1.0	T
Vest4		0.019
ClinPred		0.0018	T
GERP RS		2.5
Varity_R		0.065
gMVP		0.14
Mutation Taster		=99/1	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: rs164075; hg19: chr5-141336264; COSMIC: COSV51525127; COSMIC: COSV51525127;