chrX-91878197-C-T

Variant names:

• chrX-91878197-C-T
• rs1183327417
• NM_032968.5:c.1957C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032968.5(PCDH11X):​c.1957C>T​(p.Arg653Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R653H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18252552).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032968.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH11X	NM_032968.5	MANE Select	c.1957C>T	p.Arg653Cys	missense	Exon 6 of 11	NP_116750.1	Q9BZA7-1
	PCDH11X	NM_001168360.1		c.1957C>T	p.Arg653Cys	missense	Exon 2 of 6	NP_001161832.1	Q9BZA7-8
	PCDH11X	NM_032969.4		c.1957C>T	p.Arg653Cys	missense	Exon 2 of 6	NP_116751.1	Q9BZA7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH11X	ENST00000682573.1	MANE Select	c.1957C>T	p.Arg653Cys	missense	Exon 6 of 11	ENSP00000507225.1	Q9BZA7-1
	PCDH11X	ENST00000373094.5	TSL:1	c.1957C>T	p.Arg653Cys	missense	Exon 2 of 7	ENSP00000362186.1	Q9BZA7-1
	PCDH11X	ENST00000406881.3	TSL:1	c.1957C>T	p.Arg653Cys	missense	Exon 2 of 6	ENSP00000384758.1	Q9BZA7-8

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 3 AN: 1095079 Hom.: 0 Cov.: 29 AF XY: 0.00000555 AC XY: 2 AN XY: 360647

African (AFR) AF: 0.00 AC: 0 AN: 26346

American (AMR) AF: 0.0000284 AC: 1 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 53980

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839412

Other (OTH) AF: 0.00 AC: 0 AN: 45987

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.35	N
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.5
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.017	D
Sift4G	Benign	0.13	T
Polyphen		0.027	B
Vest4		0.16
MutPred		0.59		Loss of methylation at R653 (P = 0.0143)
MVP		0.56
MPC		1.5
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.28
gMVP		0.48
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs1183327417; hg19: chrX-91133196;