Genetic Variant NM_032968.5:c.1123C>G (chrX-91877363-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032968.5(PCDH11X):c.1123C>G(p.Pro375Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000099 ( 0 hom., 0 hem., cov: 19)

Failed GnomAD Quality Control

Consequence

PCDH11X
NM_032968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.20

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2053406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH11X	NM_032968.5 link	c.1123C>G	p.Pro375Ala	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.1123C>G	p.Pro375Ala	missense_variant	Exon 6 of 11		NM_032968.5	ENSP00000507225.1		Q9BZA7-1

Frequencies

GnomAD3 genomes

AF:

0.00000993

AC:

AN:

100695

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000993

AC:

AN:

100695

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

24045

show subpopulations

African (AFR)

AF:

0.0000363

AC:

AN:

27512

American (AMR)

AF:

0.00

AC:

AN:

8907

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2487

East Asian (EAS)

AF:

0.00

AC:

AN:

3159

South Asian (SAS)

AF:

0.00

AC:

AN:

2003

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

49891

Other (OTH)

AF:

0.00

AC:

AN:

1331

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1123C>G (p.P375A) alteration is located in exon 2 (coding exon 2) of the PCDH11X gene. This alteration results from a C to G substitution at nucleotide position 1123, causing the proline (P) at amino acid position 375 to be replaced by an alanine (A). 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

0.092

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.15

.;T;.;.;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D;D;D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;L;L;L;L;L

PhyloP100

3.2

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D

REVEL

Benign

0.097

Sift

Benign

0.23

T;T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T;T

Polyphen

0.43

B;P;B;B;B;B

Vest4

0.15

MutPred

0.58

Gain of ubiquitination at K379 (P = 0.0741);Gain of ubiquitination at K379 (P = 0.0741);Gain of ubiquitination at K379 (P = 0.0741);Gain of ubiquitination at K379 (P = 0.0741);Gain of ubiquitination at K379 (P = 0.0741);Gain of ubiquitination at K379 (P = 0.0741);

MVP

0.57

MPC

1.5

ClinPred

0.39

GERP RS

2.3

Varity_R

0.11

gMVP

0.63

Mutation Taster

=76/24

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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