rs145794638

Variant names:

• chrX-91878301-G-A
• rs145794638
• NM_032968.5:c.2061G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032968.5(PCDH11X):​c.2061G>A​(p.Pro687Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,208,256 control chromosomes in the GnomAD database, including 14 homozygotes. There are 576 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P687P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0074 (5 hom., 220 hem., cov: 20)
  • Exomes 𝑓: 0.0011 (9 hom. 356 hem.)
• Consequence: PCDH11X NM_032968.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.458
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-91878301-G-A is Benign according to our data. Variant chrX-91878301-G-A is described in ClinVar as Benign. ClinVar VariationId is 787161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.458 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00744 (820/110167) while in subpopulation AFR AF = 0.0231 (698/30272). AF 95% confidence interval is 0.0216. There are 5 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 gene

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.2061G>A	p.Pro687Pro	synonymous	Exon 6 of 11	NP_116750.1	Q9BZA7-1
	PCDH11X	NM_001168360.1		c.2061G>A	p.Pro687Pro	synonymous	Exon 2 of 6	NP_001161832.1	Q9BZA7-8
	PCDH11X	NM_032969.4		c.2061G>A	p.Pro687Pro	synonymous	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.2061G>A	p.Pro687Pro	synonymous	Exon 6 of 11	ENSP00000507225.1	Q9BZA7-1
	PCDH11X	ENST00000373094.5	TSL:1	c.2061G>A	p.Pro687Pro	synonymous	Exon 2 of 7	ENSP00000362186.1	Q9BZA7-1
	PCDH11X	ENST00000406881.3	TSL:1	c.2061G>A	p.Pro687Pro	synonymous	Exon 2 of 6	ENSP00000384758.1	Q9BZA7-8

Frequencies

GnomAD3 genomes AF: 0.00743 AC: 818 AN: 110111 Hom.: 5 Cov.: 20

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00858

Gnomad NFE AF: 0.000549

Gnomad OTH AF: 0.00609

GnomAD2 exomes AF: 0.00232 AC: 426 AN: 183279 AF XY: 0.00177

Gnomad AFR exome AF: 0.0239

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00112 AC: 1231 AN: 1098089 Hom.: 9 Cov.: 31 AF XY: 0.000979 AC XY: 356 AN XY: 363565

African (AFR) AF: 0.0256 AC: 675 AN: 26397

American (AMR) AF: 0.00168 AC: 59 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00665 AC: 129 AN: 19384

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30205

South Asian (SAS) AF: 0.000240 AC: 13 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00194 AC: 8 AN: 4132

European-Non Finnish (NFE) AF: 0.000260 AC: 219 AN: 842007

Other (OTH) AF: 0.00269 AC: 124 AN: 46086

GnomAD4 genome AF: 0.00744 AC: 820 AN: 110167 Hom.: 5 Cov.: 20 AF XY: 0.00679 AC XY: 220 AN XY: 32409

African (AFR) AF: 0.0231 AC: 698 AN: 30272

American (AMR) AF: 0.00615 AC: 63 AN: 10246

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 19 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3481

South Asian (SAS) AF: 0.00 AC: 0 AN: 2525

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5750

Middle Eastern (MID) AF: 0.00939 AC: 2 AN: 213

European-Non Finnish (NFE) AF: 0.000549 AC: 29 AN: 52863

Other (OTH) AF: 0.00601 AC: 9 AN: 1497

Alfa AF: 0.00458 Hom.: 24

Bravo AF: 0.00798

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.91
DANN	Benign	0.44
PhyloP100		0.46
Mutation Taster		=98/2	polymorphism (auto)

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: rs145794638; hg19: chrX-91133300; COSMIC: COSV53460892;