rs164077

Positions:

• chr5-141957660-A-G
• chr5-141957660-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016580.4(PCDH12):​c.192T>C​(p.Ala64Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 1,613,928 control chromosomes in the GnomAD database, including 516,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (42083 hom., cov: 32)
  • Exomes 𝑓: 0.80 (474895 hom.)
• Consequence: PCDH12 NM_016580.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.711

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-141957660-A-G is Benign according to our data. Variant chr5-141957660-A-G is described in ClinVar as [Benign]. Clinvar id is 1168162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH12	NM_016580.4	c.192T>C	p.Ala64Ala	synonymous_variant	1/4	ENST00000231484.4	NP_057664.1
RNF14	XM_047417904.1	c.-181+8250A>G		intron_variant			XP_047273860.1
RNF14	XM_047417908.1	c.-181+8250A>G		intron_variant			XP_047273864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH12	ENST00000231484.4	c.192T>C	p.Ala64Ala	synonymous_variant	1/4	1	NM_016580.4	ENSP00000231484.3

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111165 AN: 151984 Hom.: 42062 Cov.: 32

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.758

GnomAD3 exomes AF: 0.808 AC: 202808 AN: 251098 Hom.: 83059 AF XY: 0.812 AC XY: 110220 AN XY: 135784

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.877

Gnomad ASJ exome AF: 0.748

Gnomad EAS exome AF: 0.965

Gnomad SAS exome AF: 0.837

Gnomad FIN exome AF: 0.813

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.804 AC: 1174995 AN: 1461826 Hom.: 474895 Cov.: 66 AF XY: 0.805 AC XY: 585540 AN XY: 727212

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.747

Gnomad4 EAS exome AF: 0.973

Gnomad4 SAS exome AF: 0.835

Gnomad4 FIN exome AF: 0.814

Gnomad4 NFE exome AF: 0.803

Gnomad4 OTH exome AF: 0.791

GnomAD4 genome AF: 0.731 AC: 111226 AN: 152102 Hom.: 42083 Cov.: 32 AF XY: 0.737 AC XY: 54826 AN XY: 74366

Gnomad4 AFR AF: 0.520

Gnomad4 AMR AF: 0.803

Gnomad4 ASJ AF: 0.742

Gnomad4 EAS AF: 0.966

Gnomad4 SAS AF: 0.826

Gnomad4 FIN AF: 0.810

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.755

Alfa AF: 0.772 Hom.: 27986

Bravo AF: 0.720

Asia WGS AF: 0.840 AC: 2921 AN: 3478

EpiCase AF: 0.794

EpiControl AF: 0.791

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Diencephalic-mesencephalic junction dysplasia syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.65

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

Other links and lift over

dbSNP: rs164077; hg19: chr5-141337225;