Variant chr5-141854325-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032420.5(PCDH1):c.3431G>A(p.Arg1144Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PCDH1
NM_032420.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

Variant links:

Genes affected

PCDH1 (HGNC:8655): (protocadherin 1) This gene belongs to the protocadherin subfamily within the cadherin superfamily. The encoded protein is a membrane protein found at cell-cell boundaries. It is involved in neural cell adhesion, suggesting a possible role in neuronal development. The protein includes an extracelllular region, containing 7 cadherin-like domains, a transmembrane region and a C-terminal cytoplasmic region. Cells expressing the protein showed cell aggregation activity. Alternative splicing occurs in this gene. [provided by RefSeq, Jul 2008]

PCDH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21118242).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5 linkuse as main transcript	c.3431G>A	p.Arg1144Gln	missense_variant	5/5	ENST00000287008.8	NP_115796.2	Q08174-2B4E2D8
PCDH1	XM_005268452.4 linkuse as main transcript	c.3479G>A	p.Arg1160Gln	missense_variant	5/5		XP_005268509.2
PCDH1	XM_017009517.3 linkuse as main transcript	c.2294G>A	p.Arg765Gln	missense_variant	4/4		XP_016865006.1
PCDH1	XM_005268454.6 linkuse as main transcript	c.*125G>A		3_prime_UTR_variant	6/6		XP_005268511.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH1	ENST00000287008.8 linkuse as main transcript	c.3431G>A	p.Arg1144Gln	missense_variant	5/5	5	NM_032420.5	ENSP00000287008.3		Q08174-2
PCDH1	ENST00000503492 linkuse as main transcript	c.*125G>A		3_prime_UTR_variant	5/5	5		ENSP00000424667.1		D6RAX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248898

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135098

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The c.3431G>A (p.R1144Q) alteration is located in exon 5 (coding exon 5) of the PCDH1 gene. This alteration results from a G to A substitution at nucleotide position 3431, causing the arginine (R) at amino acid position 1144 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.47

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.013

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.76

REVEL

Benign

0.075

Sift

Benign

0.41

Sift4G

Uncertain

0.018

Polyphen

0.99

Vest4

0.11

MutPred

0.18

Loss of MoRF binding (P = 0.0287);

MVP

0.33

MPC

0.64

ClinPred

0.93

GERP RS

4.5

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over