Variant X-91835977-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032968.5(PCDH11X):c.473A>G(p.Tyr158Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,983 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

PCDH11X
NM_032968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.55

Variant links:

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]

PCDH11X links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH11X	NM_032968.5 linkuse as main transcript	c.473A>G	p.Tyr158Cys	missense_variant	5/11	ENST00000682573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH11X	ENST00000682573.1 linkuse as main transcript	c.473A>G	p.Tyr158Cys	missense_variant	5/11		NM_032968.5	P4	Q9BZA7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097983

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363507

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.473A>G (p.Y158C) alteration is located in exon 1 (coding exon 1) of the PCDH11X gene. This alteration results from a A to G substitution at nucleotide position 473, causing the tyrosine (Y) at amino acid position 158 to be replaced by a cysteine (C). 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

0.69

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;T;.;.;.;.

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.0

M;M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.0

D;D;D;D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.72

MutPred

0.53

Gain of methylation at K157 (P = 0.0167);Gain of methylation at K157 (P = 0.0167);Gain of methylation at K157 (P = 0.0167);Gain of methylation at K157 (P = 0.0167);Gain of methylation at K157 (P = 0.0167);Gain of methylation at K157 (P = 0.0167);

MVP

0.96

MPC

2.6

ClinPred

0.99

GERP RS

3.2

Varity_R

0.77

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over