dbSNP rs10492477: PCDH9:c.3138+135899T>A (chr13-66767605-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_203487.3(PCDH9):c.3138+135899T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0813 (AC=12,363) in the gnomAD database across 152,066 control chromosomes, including 524 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.131. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.081 ( 524 hom., cov: 32)

Consequence

PCDH9
NM_203487.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.492

Publications

2 publications found

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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new If you want to explore the variant's impact on the transcript NM_203487.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1310 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_203487.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCDH9	NM_203487.3	MANE Select	c.3138+135899T>A	intron	N/A	NP_982354.1	Q9HC56-1
PCDH9	NM_020403.5		c.3037-136194T>A	intron	N/A	NP_065136.1	Q9HC56-2
PCDH9	NM_001318372.2		c.3138+135899T>A	intron	N/A	NP_001305301.1	B7ZM79

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCDH9	ENST00000377865.7	TSL:1 MANE Select	c.3138+135899T>A	intron	N/A	ENSP00000367096.2	Q9HC56-1
PCDH9	ENST00000544246.5	TSL:1	c.3037-136194T>A	intron	N/A	ENSP00000442186.2	Q9HC56-2
PCDH9	ENST00000456367.5	TSL:1	c.3138+135899T>A	intron	N/A	ENSP00000401699.2	A0A0A0MST3

Frequencies

GnomAD3 genomes

AF:

0.0814

AC:

12362

AN:

151948

Hom.:

523

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0753

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.0730

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.0752

Gnomad FIN

AF:

0.0753

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0886

Gnomad OTH

AF:

0.0882

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0813

AC:

12363

AN:

152066

Hom.:

524

Cov.:

AF XY:

0.0818

AC XY:

6080

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0752

AC:

3123

AN:

41516

American (AMR)

AF:

0.0564

AC:

860

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.0730

AC:

253

AN:

3468

East Asian (EAS)

AF:

0.139

AC:

719

AN:

5156

South Asian (SAS)

AF:

0.0755

AC:

364

AN:

4820

European-Finnish (FIN)

AF:

0.0753

AC:

799

AN:

10604

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0886

AC:

6021

AN:

67932

Other (OTH)

AF:

0.0873

AC:

184

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

573

1146

1718

2291

2864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0881

Hom.:

Bravo

AF:

0.0789

Asia WGS

AF:

0.121

AC:

423

AN:

3468

Local populations

Turkish Variome

AF:

0.0718

AC:

111

AN:

1546

Hom.:

ABraOM SABE-WGS-1171

AF:

0.0730

AC:

171

AN:

2342

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over