Variant chr5-141854211-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032420.5(PCDH1):c.3545C>T(p.Thr1182Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,458,620 control chromosomes in the GnomAD database, including 1 homozygotes. 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: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

PCDH1
NM_032420.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04336509).

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH1	NM_032420.5 linkuse as main transcript	c.3545C>T	p.Thr1182Met	missense_variant	5/5	ENST00000287008.8	NP_115796.2	Q08174-2B4E2D8
PCDH1	XM_005268452.4 linkuse as main transcript	c.3593C>T	p.Thr1198Met	missense_variant	5/5		XP_005268509.2
PCDH1	XM_017009517.3 linkuse as main transcript	c.2408C>T	p.Thr803Met	missense_variant	4/4		XP_016865006.1
PCDH1	XM_005268454.6 linkuse as main transcript	c.*239C>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.3545C>T	p.Thr1182Met	missense_variant	5/5	5	NM_032420.5	ENSP00000287008.3		Q08174-2
PCDH1	ENST00000503492 linkuse as main transcript	c.*239C>T		3_prime_UTR_variant	5/5	5		ENSP00000424667.1		D6RAX3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000533

AC:

AN:

244116

Hom.:

AF XY:

0.0000378

AC XY:

AN XY:

132348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000265

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1458620

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725260

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000450

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000811

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000659

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

May 04, 2022

The c.3545C>T (p.T1182M) 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 3545, causing the threonine (T) at amino acid position 1182 to be replaced by a methionine (M). 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

-0.47

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

DANN

Benign

0.96

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.75

M_CAP

Benign

0.014

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.45

REVEL

Benign

0.14

Sift

Benign

0.19

Sift4G

Benign

0.32

Polyphen

0.0080

Vest4

0.095

MutPred

0.21

Loss of glycosylation at T1182 (P = 0.0204);

MVP

0.068

MPC

0.46

ClinPred

0.099

GERP RS

3.6

gMVP

0.31

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