rs765860336

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032968.5(PCDH11X):c.92G>A(p.Arg31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,208,927 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.000034 ( 0 hom. 9 hem. )

Consequence

PCDH11X
NM_032968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

Publications

4 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19024774).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH11X	NM_032968.5 link	c.92G>A	p.Arg31Gln	missense_variant	Exon 5 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.92G>A	p.Arg31Gln	missense_variant	Exon 5 of 11		NM_032968.5	ENSP00000507225.1		Q9BZA7-1

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000709

AC:

AN:

183432

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000312

Gnomad NFE exome

AF:

0.0000976

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1098205

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

363589

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30205

South Asian (SAS)

AF:

0.00

AC:

AN:

54145

European-Finnish (FIN)

AF:

0.000173

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000356

AC:

AN:

842124

Other (OTH)

AF:

0.00

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110722

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

32932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30512

American (AMR)

AF:

0.00

AC:

AN:

10234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3510

South Asian (SAS)

AF:

0.00

AC:

AN:

2534

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

5919

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52981

Other (OTH)

AF:

0.00

AC:

AN:

1487

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Aug 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in the literature in individuals with PCDH11X-related disease. This sequence change replaces arginine with glutamine at codon 31 of the PCDH11X protein (p.Arg31Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs765860336, ExAC 0.02%). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0084

.;T;.;.;.;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;L;L;L;L

PhyloP100

3.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.11

N;N;N;N;N;N

REVEL

Benign

0.084

Sift

Benign

0.24

T;T;T;T;T;T

Sift4G

Uncertain

0.026

D;D;D;D;D;D

Polyphen

1.0

D;D;P;D;D;D

Vest4

0.12

MVP

0.65

MPC

1.9

ClinPred

0.18

GERP RS

1.9

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.069

gMVP

0.60

Mutation Taster

=100/0

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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rs765860336

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over