13-66304735-T-C

Variant names:

• chr13-66304735-T-C
• NM_203487.3:c.3634A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_203487.3(PCDH9):​c.3634A>G​(p.Thr1212Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH9 NM_203487.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.83
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043413103).

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.3634A>G	p.Thr1212Ala	missense	Exon 5 of 5	NP_982354.1	X5D7N0
	PCDH9	NM_020403.5		c.3532A>G	p.Thr1178Ala	missense	Exon 4 of 4	NP_065136.1	Q9HC56-2
	PCDH9	NM_001318372.2		c.3508A>G	p.Thr1170Ala	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.3634A>G	p.Thr1212Ala	missense	Exon 5 of 5	ENSP00000367096.2	Q9HC56-1
	PCDH9	ENST00000544246.5	TSL:1	c.3532A>G	p.Thr1178Ala	missense	Exon 4 of 4	ENSP00000442186.2	Q9HC56-2
	PCDH9	ENST00000456367.5	TSL:1	c.3508A>G	p.Thr1170Ala	missense	Exon 5 of 5	ENSP00000401699.2	B7ZM79

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.058
Sift	Benign	0.38	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.037
MutPred		0.28		Gain of catalytic residue at D1213 (P = 0.001)
MVP		0.11
MPC		0.29
ClinPred		0.065	T
GERP RS		2.4
Varity_R		0.035
gMVP		0.18
Mutation Taster		=84/16	polymorphism

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: chr13-66878867;