X-91878335-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032968.5(PCDH11X):c.2095A>C(p.Ile699Leu) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

Genes affected

PCDH11X (HGNC:8656): (protocadherin 11 X-linked) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The encoded protein consists of an extracellular domain containing 7 cadherin repeats, a transmembrane domain and a cytoplasmic tail that differs from those of the classical cadherins. The gene is located in a major X/Y block of homology and its Y homolog, despite divergence leading to coding region changes, is the most closely related cadherin family member. The protein is thought to play a fundamental role in cell-cell recognition essential for the segmental development and function of the central nervous system. Disruption of this gene may be associated with developmental dyslexia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08250031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH11X	NM_032968.5	c.2095A>C	p.Ile699Leu	missense_variant	6/11	ENST00000682573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH11X	ENST00000682573.1	c.2095A>C	p.Ile699Leu	missense_variant	6/11		NM_032968.5	P4

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 20

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

Oct 27, 2021

The c.2095A>C (p.I699L) alteration is located in exon 2 (coding exon 2) of the PCDH11X gene. This alteration results from a A to C substitution at nucleotide position 2095, causing the isoleucine (I) at amino acid position 699 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	Benign	0.085
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	6.5
Dann	Benign	0.54
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.67	T;T;T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.083	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.010	N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.040	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.70	T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.10
MutPred		0.47		Gain of catalytic residue at I699 (P = 0.1436);Gain of catalytic residue at I699 (P = 0.1436);Gain of catalytic residue at I699 (P = 0.1436);Gain of catalytic residue at I699 (P = 0.1436);Gain of catalytic residue at I699 (P = 0.1436);Gain of catalytic residue at I699 (P = 0.1436);
MVP		0.22
MPC		1.1
ClinPred		0.048	T
GERP RS		-6.6
Varity_R		0.084
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-91133334;