Variant X-91878198-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_032968.5(PCDH11X):c.1958G>A(p.Arg653His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000639 in 1,095,168 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000064 ( 0 hom. 1 hem. )

Consequence

PCDH11X
NM_032968.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.643

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12628284).

BP6

Variant X-91878198-G-A is Benign according to our data. Variant chrX-91878198-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2226449.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH11X	NM_032968.5 linkuse as main transcript	c.1958G>A	p.Arg653His	missense_variant	6/11	ENST00000682573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH11X	ENST00000682573.1 linkuse as main transcript	c.1958G>A	p.Arg653His	missense_variant	6/11		NM_032968.5	P4	Q9BZA7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1095168

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

360692

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:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.3

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

.;T;.;.;.;.

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.93

D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

L;L;L;L;L;L

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D

REVEL

Benign

0.11

Sift

Benign

0.087

T;T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.012

B;B;B;B;B;B

Vest4

0.055

MutPred

0.65

Loss of methylation at R653 (P = 0.0143);Loss of methylation at R653 (P = 0.0143);Loss of methylation at R653 (P = 0.0143);Loss of methylation at R653 (P = 0.0143);Loss of methylation at R653 (P = 0.0143);Loss of methylation at R653 (P = 0.0143);

MVP

0.59

MPC

1.4

ClinPred

0.080

GERP RS

-0.57

Varity_R

0.11

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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