Variant 5-141854232-G-A 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.3524C>T(p.Pro1175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,610,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PCDH1
NM_032420.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.30

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=0.07204059).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5 linkuse as main transcript	c.3524C>T	p.Pro1175Leu	missense_variant	5/5	ENST00000287008.8	NP_115796.2	Q08174-2B4E2D8
PCDH1	XM_005268452.4 linkuse as main transcript	c.3572C>T	p.Pro1191Leu	missense_variant	5/5		XP_005268509.2
PCDH1	XM_017009517.3 linkuse as main transcript	c.2387C>T	p.Pro796Leu	missense_variant	4/4		XP_016865006.1
PCDH1	XM_005268454.6 linkuse as main transcript	c.*218C>T		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.3524C>T	p.Pro1175Leu	missense_variant	5/5	5	NM_032420.5	ENSP00000287008.3		Q08174-2
PCDH1	ENST00000503492 linkuse as main transcript	c.*218C>T		3_prime_UTR_variant	5/5	5		ENSP00000424667.1		D6RAX3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

240948

Hom.:

AF XY:

0.0000381

AC XY:

AN XY:

131206

show subpopulations

Gnomad AFR exome

AF:

0.000202

Gnomad AMR exome

AF:

0.0000590

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000664

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1458700

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725476

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.0000677

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000495

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

Jun 07, 2024

The c.3524C>T (p.P1175L) alteration is located in exon 5 (coding exon 5) of the PCDH1 gene. This alteration results from a C to T substitution at nucleotide position 3524, causing the proline (P) at amino acid position 1175 to be replaced by a leucine (L). 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

-0.40

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

DANN

Benign

0.97

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.016

MetaRNN

Benign

0.072

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.97

REVEL

Benign

0.038

Sift

Benign

0.18

Sift4G

Benign

0.29

Polyphen

0.013

Vest4

0.14

MutPred

0.32

Loss of glycosylation at P1175 (P = 0.0143);

MVP

0.10

MPC

0.51

ClinPred

0.097

GERP RS

2.9

gMVP

0.28

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

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