13-57633237-G-T

Position:

• chr13-57633237-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001040429.3(PCDH17):​c.691G>T​(p.Val231Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCDH17 NM_001040429.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

Genes affected

PCDH17 (HGNC:14267): (protocadherin 17) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein contains six extracellular cadherin domains, a transmembrane domain, and a cytoplasmic tail differing from those of the classical cadherins. The encoded protein may play a role in the establishment and function of specific cell-cell connections in the brain. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH17	NM_001040429.3	c.691G>T	p.Val231Leu	missense_variant	1/4	ENST00000377918.8
PCDH17	XM_005266357.3	c.691G>T	p.Val231Leu	missense_variant	2/5
PCDH17	XM_047430276.1	c.691G>T	p.Val231Leu	missense_variant	2/5
PCDH17	XM_017020547.2	c.691G>T	p.Val231Leu	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH17	ENST00000377918.8	c.691G>T	p.Val231Leu	missense_variant	1/4	1	NM_001040429.3	P1
	ENST00000610846.1	n.339C>A		non_coding_transcript_exon_variant	1/2	4
PCDH17	ENST00000484979.5	c.691G>T	p.Val231Leu	missense_variant, NMD_transcript_variant	1/4	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.691G>T (p.V231L) alteration is located in exon 1 (coding exon 1) of the PCDH17 gene. This alteration results from a G to T substitution at nucleotide position 691, causing the valine (V) at amino acid position 231 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.013	D
Polyphen		0.95	P
Vest4		0.48
MutPred		0.54		Gain of catalytic residue at S236 (P = 0.0166);
MVP		0.66
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.75
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs1954756398; hg19: chr13-58207371;