Genetic Variant PCDH11X:p.Ala339Ser (chrX-91877255-G-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032968.5(PCDH11X):c.1015G>T(p.Ala339Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 15)

Exomes 𝑓: 0.0000010 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

PCDH11X
NM_032968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.51

Publications

2 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.39266312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH11X	NM_032968.5 link	c.1015G>T	p.Ala339Ser	missense_variant	Exon 6 of 11	ENST00000682573.1	NP_116750.1	Q9BZA7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH11X	ENST00000682573.1 link	c.1015G>T	p.Ala339Ser	missense_variant	Exon 6 of 11		NM_032968.5	ENSP00000507225.1		Q9BZA7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000102

AC:

AN:

980924

Hom.:

Cov.:

AF XY:

0.00000347

AC XY:

AN XY:

287836

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23865

American (AMR)

AF:

0.00

AC:

AN:

32105

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18205

East Asian (EAS)

AF:

0.00

AC:

AN:

28429

South Asian (SAS)

AF:

0.00

AC:

AN:

49197

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3758

European-Non Finnish (NFE)

AF:

0.00000134

AC:

AN:

745962

Other (OTH)

AF:

0.00

AC:

AN:

42193

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000885

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 25, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1015G>T (p.A339S) alteration is located in exon 2 (coding exon 2) of the PCDH11X gene. This alteration results from a G to T substitution at nucleotide position 1015, causing the alanine (A) at amino acid position 339 to be replaced by a serine (S). 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

0.20

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

.;T;.;.;.;.

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Benign

0.055

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.74

N;N;N;N;N;N

PhyloP100

6.5

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Uncertain

0.017

D;D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D;D

Polyphen

1.0

D;D;B;D;D;D

Vest4

0.26

MutPred

0.71

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.61

MPC

1.7

ClinPred

0.97

GERP RS

4.3

Varity_R

0.57

gMVP

0.69

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over