5-141957660-A-G

Variant names:

• chr5-141957660-A-G
• rs164077
• NM_016580.4:c.192T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016580.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH12	NM_016580.4	MANE Select	c.192T>C	p.Ala64Ala	synonymous	Exon 1 of 4	NP_057664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH12	ENST00000231484.4	TSL:1 MANE Select	c.192T>C	p.Ala64Ala	synonymous	Exon 1 of 4	ENSP00000231484.3
	PCDH12	ENST00000510041.1	TSL:4	c.*121T>C		downstream_gene	N/A	ENSP00000429094.1

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

GnomAD2 exomes AF: 0.808 AC: 202808 AN: 251098 AF XY: 0.812

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 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

African (AFR) AF: 0.513 AC: 17164 AN: 33480

American (AMR) AF: 0.869 AC: 38870 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 19516 AN: 26132

East Asian (EAS) AF: 0.973 AC: 38612 AN: 39700

South Asian (SAS) AF: 0.835 AC: 72018 AN: 86258

European-Finnish (FIN) AF: 0.814 AC: 43452 AN: 53410

Middle Eastern (MID) AF: 0.771 AC: 4448 AN: 5768

European-Non Finnish (NFE) AF: 0.803 AC: 893154 AN: 1111964

Other (OTH) AF: 0.791 AC: 47761 AN: 60392

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

African (AFR) AF: 0.520 AC: 21556 AN: 41444

American (AMR) AF: 0.803 AC: 12274 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2575 AN: 3472

East Asian (EAS) AF: 0.966 AC: 5000 AN: 5176

South Asian (SAS) AF: 0.826 AC: 3982 AN: 4822

European-Finnish (FIN) AF: 0.810 AC: 8579 AN: 10586

Middle Eastern (MID) AF: 0.714 AC: 210 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54764 AN: 67992

Other (OTH) AF: 0.755 AC: 1594 AN: 2112

Alfa AF: 0.769 Hom.: 31268

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2020

GeneDx

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.0
DANN	Benign	0.65
PhyloP100		-0.71
Mutation Taster		=100/0	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: rs164077; hg19: chr5-141337225; COSMIC: COSV99186647; COSMIC: COSV99186647;