rs574087581

chr5-141955118-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP6 BS1

The NM_016580.4(PCDH12):c.2734C>T(p.Arg912Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PCDH12 NM_016580.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.06

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:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-141955118-G-A is Benign according to our data. Variant chr5-141955118-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587639.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000108 (158/1461892) while in subpopulation SAS AF= 0.000719 (62/86258). AF 95% confidence interval is 0.000575. There are 0 homozygotes in gnomad4_exome. There are 98 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH12	NM_016580.4	c.2734C>T	p.Arg912Trp	missense_variant	1/4	ENST00000231484.4
RNF14	XM_047417904.1	c.-181+5708G>A		intron_variant
RNF14	XM_047417908.1	c.-181+5708G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH12	ENST00000231484.4	c.2734C>T	p.Arg912Trp	missense_variant	1/4	1	NM_016580.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 250948 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000988 AC: 12

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Diencephalic-mesencephalic junction dysplasia syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.88	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.85
MPC		0.74
ClinPred		0.21	T
GERP RS		2.1
Varity_R		0.18
gMVP		0.76

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: rs574087581; hg19: chr5-141334683; COSMIC: COSV51522153; COSMIC: COSV51522153;