ENST00000377861.4:c.3059C>A

Variant names:

• chr13-67225382-G-T
• ENST00000377861.4:c.3059C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000377861.4(PCDH9):​c.3059C>A​(p.Ser1020Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDH9 ENST00000377861.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.52
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000377861.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH9	NM_203487.3	MANE Select	c.3036+23C>A		intron	N/A	NP_982354.1	X5D7N0
	PCDH9	NM_001318374.2		c.3059C>A	p.Ser1020Tyr	missense	Exon 2 of 2	NP_001305303.1	Q5VT82
	PCDH9	NM_020403.5		c.3036+23C>A		intron	N/A	NP_065136.1	Q9HC56-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH9	ENST00000377861.4	TSL:1	c.3059C>A	p.Ser1020Tyr	missense	Exon 2 of 2	ENSP00000367092.3	Q5VT82
	PCDH9	ENST00000377865.7	TSL:1 MANE Select	c.3036+23C>A		intron	N/A	ENSP00000367096.2	Q9HC56-1
	PCDH9	ENST00000544246.5	TSL:1	c.3036+23C>A		intron	N/A	ENSP00000442186.2	Q9HC56-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454820 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724222

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106134

Other (OTH) AF: 0.00 AC: 0 AN: 60086

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	PCDH9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.024	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.40	T
PhyloP100		9.5
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.26
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.012	D
Polyphen		0.97	D
Vest4		0.73
MutPred		0.41		Gain of catalytic residue at S1020 (P = 8e-04)
MVP		0.31
ClinPred		0.58	D
GERP RS		5.3
Mutation Taster		=37/63	disease causing

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

Other links and lift over

hg19: chr13-67799514;