X-91877898-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_032968.5(PCDH11X):c.1658A>C(p.Asn553Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N553D) has been classified 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: 9.04

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 4 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity PC11X_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH11X	NM_032968.5	c.1658A>C	p.Asn553Thr	missense_variant	6/11	ENST00000682573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH11X	ENST00000682573.1	c.1658A>C	p.Asn553Thr	missense_variant	6/11		NM_032968.5	P4

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 32

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

Dec 15, 2022

The c.1658A>C (p.N553T) 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 1658, causing the asparagine (N) at amino acid position 553 to be replaced by a threonine (T). 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	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	14
Dann	Benign	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T;T;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.92	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		1.0	D;D;P;D;D;D
Vest4		0.59
MutPred		0.41		Gain of glycosylation at S552 (P = 0.1541);Gain of glycosylation at S552 (P = 0.1541);Gain of glycosylation at S552 (P = 0.1541);Gain of glycosylation at S552 (P = 0.1541);Gain of glycosylation at S552 (P = 0.1541);Gain of glycosylation at S552 (P = 0.1541);
MVP		0.82
MPC		2.2
ClinPred		0.54	D
GERP RS		5.4
Varity_R		0.29
gMVP		0.33

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-91132897;