chr13-67225575-C-G

Variant names:

Variant summary

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

The NM_203487.3(PCDH9):c.2866G>C(p.Val956Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000781 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

PCDH9
NM_203487.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

Variant links:

Genes affected

PCDH9 (HGNC:8661): (protocadherin 9) This gene encodes a member of the protocadherin family, and cadherin superfamily, of transmembrane proteins containing cadherin domains. These proteins mediate cell adhesion in neural tissues in the presence of calcium. The encoded protein may be involved in signaling at neuronal synaptic junctions. Sharing a characteristic with other protocadherin genes, this gene has a notably large exon that encodes multiple cadherin domains and a transmembrane region. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Nov 2012]

PCDH9 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11940235).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH9	NM_203487.3 link	c.2866G>C	p.Val956Leu	missense_variant	Exon 2 of 5	ENST00000377865.7	NP_982354.1	Q9HC56-1X5D7N0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCDH9	ENST00000377865.7 link	c.2866G>C	p.Val956Leu	missense_variant	Exon 2 of 5	1	NM_203487.3	ENSP00000367096.2	Q9HC56-1
PCDH9	ENST00000544246.5 link	c.2866G>C	p.Val956Leu	missense_variant	Exon 2 of 4	1		ENSP00000442186.2	Q9HC56-2
PCDH9	ENST00000456367.5 link	c.2866G>C	p.Val956Leu	missense_variant	Exon 2 of 5	1		ENSP00000401699.2	B7ZM79
PCDH9	ENST00000377861.4 link	c.2866G>C	p.Val956Leu	missense_variant	Exon 2 of 2	1		ENSP00000367092.3	Q5VT82

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00949

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251444

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000602

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2866G>C (p.V956L) alteration is located in exon 2 (coding exon 1) of the PCDH9 gene. This alteration results from a G to C substitution at nucleotide position 2866, causing the valine (V) at amino acid position 956 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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0079

T;.;T;T

Eigen

Benign

-0.028

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.80

N;N;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.46

N;N;N;N

REVEL

Benign

0.074

Sift

Benign

0.59

T;T;T;T

Sift4G

Benign

0.86

T;T;T;T

Polyphen

0.095

B;B;B;B

Vest4

0.48

MutPred

0.41

Gain of catalytic residue at K959 (P = 0.0028);Gain of catalytic residue at K959 (P = 0.0028);Gain of catalytic residue at K959 (P = 0.0028);Gain of catalytic residue at K959 (P = 0.0028);

MVP

0.12

MPC

0.31

ClinPred

0.056

GERP RS

4.7

Varity_R

0.14

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