X-91877043-T-G

Variant names:

• chrX-91877043-T-G
• NM_032968.5:c.803T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032968.5(PCDH11X):​c.803T>G​(p.Val268Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH11X	NM_032968.5	c.803T>G	p.Val268Gly	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.803T>G	p.Val268Gly	missense_variant	Exon 6 of 11		NM_032968.5	ENSP00000507225.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803T>G (p.V268G) alteration is located in exon 2 (coding exon 2) of the PCDH11X gene. This alteration results from a T to G substitution at nucleotide position 803, causing the valine (V) at amino acid position 268 to be replaced by a glycine (G). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;H;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.71
MutPred		0.78		Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);Gain of disorder (P = 0.0214);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.89

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-91132042;