Variant chr13-67225617-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203487.3(PCDH9):c.2824G>A(p.Ala942Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PCDH9
NM_203487.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH9	NM_203487.3 linkuse as main transcript	c.2824G>A	p.Ala942Thr	missense_variant	2/5	ENST00000377865.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH9	ENST00000377865.7 linkuse as main transcript	c.2824G>A	p.Ala942Thr	missense_variant	2/5	1	NM_203487.3		Q9HC56-1
PCDH9	ENST00000544246.5 linkuse as main transcript	c.2824G>A	p.Ala942Thr	missense_variant	2/4	1		P1	Q9HC56-2
PCDH9	ENST00000456367.5 linkuse as main transcript	c.2824G>A	p.Ala942Thr	missense_variant	2/5	1
PCDH9	ENST00000377861.4 linkuse as main transcript	c.2824G>A	p.Ala942Thr	missense_variant	2/2	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251474

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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 22, 2021

The c.2824G>A (p.A942T) alteration is located in exon 2 (coding exon 1) of the PCDH9 gene. This alteration results from a G to A substitution at nucleotide position 2824, causing the alanine (A) at amino acid position 942 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

0.00050

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0089

T;.;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.040

N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.37

T;T;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.93

P;P;P;P

Vest4

0.75

MutPred

0.37

Gain of glycosylation at A942 (P = 0.0394);Gain of glycosylation at A942 (P = 0.0394);Gain of glycosylation at A942 (P = 0.0394);Gain of glycosylation at A942 (P = 0.0394);

MVP

0.41

MPC

0.60

ClinPred

0.49

GERP RS

5.7

Varity_R

0.16

gMVP

0.46

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