X-91876893-A-G

Variant names:

• chrX-91876893-A-G
• rs766698792
• NM_032968.5:c.653A>G

Variant summary

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

The NM_032968.5(PCDH11X):​c.653A>G​(p.Lys218Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K218I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 20)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.04
• Publications: 0 publications found

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

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH11X	NM_032968.5	c.653A>G	p.Lys218Arg	missense_variant	Exon 6 of 11	ENST00000682573.1	NP_116750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH11X	ENST00000682573.1	c.653A>G	p.Lys218Arg	missense_variant	Exon 6 of 11		NM_032968.5	ENSP00000507225.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.57	N;N;N;N;N;N
PhyloP100		9.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.86	N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.11	T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.47
MutPred		0.41		Loss of ubiquitination at K218 (P = 0.0183);Loss of ubiquitination at K218 (P = 0.0183);Loss of ubiquitination at K218 (P = 0.0183);Loss of ubiquitination at K218 (P = 0.0183);Loss of ubiquitination at K218 (P = 0.0183);Loss of ubiquitination at K218 (P = 0.0183);
MVP		0.80
MPC		2.1
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.46
gMVP		0.60
Mutation Taster		=64/36	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

dbSNP: rs766698792; hg19: chrX-91131892;