13-66305008-C-T

Variant names:

• chr13-66305008-C-T
• rs753950672
• NM_203487.3:c.3361G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_203487.3(PCDH9):​c.3361G>A​(p.Gly1121Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PCDH9 NM_203487.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• 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]

PCDH9-AS1 (HGNC:39897): (PCDH9 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3124609).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203487.3. 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.3361G>A	p.Gly1121Arg	missense	Exon 5 of 5	NP_982354.1	X5D7N0
	PCDH9	NM_020403.5		c.3259G>A	p.Gly1087Arg	missense	Exon 4 of 4	NP_065136.1	Q9HC56-2
	PCDH9	NM_001318372.2		c.3235G>A	p.Gly1079Arg	missense	Exon 5 of 5	NP_001305301.1	B7ZM79

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH9	ENST00000377865.7	TSL:1 MANE Select	c.3361G>A	p.Gly1121Arg	missense	Exon 5 of 5	ENSP00000367096.2	Q9HC56-1
	PCDH9	ENST00000544246.5	TSL:1	c.3259G>A	p.Gly1087Arg	missense	Exon 4 of 4	ENSP00000442186.2	Q9HC56-2
	PCDH9	ENST00000456367.5	TSL:1	c.3235G>A	p.Gly1079Arg	missense	Exon 5 of 5	ENSP00000401699.2	B7ZM79

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458932 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725394

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110034

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.32
Sift	Benign	0.077	T
Sift4G	Benign	0.22	T
Polyphen		0.54	P
Vest4		0.62
MutPred		0.13		Gain of helix (P = 0.0854)
MVP		0.44
MPC		0.82
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.082
gMVP		0.55
Mutation Taster		=46/54	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

dbSNP: rs753950672; hg19: chr13-66879140;