NM_032968.5:c.653A>T

Variant names:

• chrX-91876893-A-T
• rs766698792
• NM_032968.5:c.653A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032968.5(PCDH11X):​c.653A>T​(p.Lys218Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 20)
• Consequence: PCDH11X NM_032968.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.04
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.653A>T	p.Lys218Ile	missense	Exon 6 of 11	NP_116750.1	Q9BZA7-1
	PCDH11X	NM_001168360.1		c.653A>T	p.Lys218Ile	missense	Exon 2 of 6	NP_001161832.1	Q9BZA7-8
	PCDH11X	NM_032969.4		c.653A>T	p.Lys218Ile	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.653A>T	p.Lys218Ile	missense	Exon 6 of 11	ENSP00000507225.1	Q9BZA7-1
	PCDH11X	ENST00000373094.5	TSL:1	c.653A>T	p.Lys218Ile	missense	Exon 2 of 7	ENSP00000362186.1	Q9BZA7-1
	PCDH11X	ENST00000406881.3	TSL:1	c.653A>T	p.Lys218Ile	missense	Exon 2 of 6	ENSP00000384758.1	Q9BZA7-8

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0066	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.23	N
PhyloP100		9.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.26
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.48		Loss of disorder (P = 0.0091)
MVP		0.76
MPC		3.1
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.75
Mutation Taster		=60/40	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: rs766698792; hg19: chrX-91131892;