13-66903591-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_203487.3(PCDH9):c.3051C>A(p.Ser1017Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,507,656 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (9 hom.)
• Consequence: PCDH9 NM_203487.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.77

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-AS2 (HGNC:39896): (PCDH9 antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070990026).
• BP6: Variant 13-66903591-G-T is Benign according to our data. Variant chr13-66903591-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2643837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH9	NM_203487.3	c.3051C>A	p.Ser1017Arg	missense_variant	3/5	ENST00000377865.7
PCDH9-AS2	NR_046527.1	n.355-10807G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH9	ENST00000377865.7	c.3051C>A	p.Ser1017Arg	missense_variant	3/5	1	NM_203487.3
PCDH9-AS2	ENST00000419371.2	n.355-10807G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 151828 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00457

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00170

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00189 AC: 466 AN: 246700 Hom.: 3 AF XY: 0.00222 AC XY: 297 AN XY: 133514

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.000952

Gnomad ASJ exome AF: 0.00242

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.00713

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00235

GnomAD4 exome AF: 0.00155 AC: 2107 AN: 1355710 Hom.: 9 Cov.: 20 AF XY: 0.00176 AC XY: 1200 AN XY: 680262

Gnomad4 AFR exome AF: 0.0000968

Gnomad4 AMR exome AF: 0.000976

Gnomad4 ASJ exome AF: 0.00277

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.00697

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00115 AC: 174 AN: 151946 Hom.: 1 Cov.: 32 AF XY: 0.000956 AC XY: 71 AN XY: 74274

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000722

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00478

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00170

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.000774 Hom.: 0

Bravo AF: 0.00104

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PCDH9: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0072	T;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0071	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.010	N;.
REVEL	Benign	0.089
Sift	Benign	0.31	T;.
Sift4G	Benign	0.20	T;T
Polyphen		0.83	P;B
Vest4		0.66
MutPred		0.25		Gain of catalytic residue at N1021 (P = 0.0024);Gain of catalytic residue at N1021 (P = 0.0024);
MVP		0.19
ClinPred		0.016	T
GERP RS		5.5
Varity_R		0.18
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs149470963; hg19: chr13-67477723;