5-141956699-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016580.4(PCDH12):​c.1153C>G​(p.His385Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H385N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCDH12 NM_016580.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059523255).

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.1153C>G	p.His385Asp	missense	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.1153C>G	p.His385Asp	missense	Exon 1 of 4	ENSP00000231484.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.037	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N
PhyloP100		0.0020
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.022
Sift	Benign	0.62	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.046
MutPred		0.20		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.14
MPC		0.25
ClinPred		0.13	T
GERP RS		2.5
Varity_R		0.097
gMVP		0.27
Mutation Taster		=93/7	polymorphism

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;