X-101109936-C-A

Variant names:

• chrX-101109936-C-A
• rs775674652
• NM_001386188.2:c.529C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001386188.2(CENPI):​c.529C>A​(p.Arg177Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,094,313 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R177C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000082 (0 hom. 4 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• Publications: 0 publications found

Genes affected

CENPI (HGNC:3968): (centromere protein I) This gene encodes a centromere protein that is a component of the CENPA-NAC (nucleosome-associated) complex. This complex is critical for accurate chromosome alignment and segregation and it ensures proper mitotic progression. This protein regulates the recruitment of kinetochore-associated proteins that are required to generate the spindle checkpoint signal. The product of this gene is involved in the response of gonadal tissues to follicle-stimulating hormone. Mutations in this gene may be involved in human X-linked disorders of gonadal development and gametogenesis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 13. [provided by RefSeq, Jan 2016]

CENPI Gene-Disease associations (from GenCC):

• idiopathic steroid-sensitive nephrotic syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10446465).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386188.2. 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
	CENPI	NM_001386188.2	MANE Select	c.529C>A	p.Arg177Ser	missense	Exon 6 of 22	NP_001373117.1	Q92674-1
	CENPI	NM_006733.3		c.529C>A	p.Arg177Ser	missense	Exon 5 of 21	NP_006724.2	Q92674-1
	CENPI	NM_001318521.2		c.529C>A	p.Arg177Ser	missense	Exon 6 of 21	NP_001305450.1	A0A8C8KX99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPI	ENST00000682095.1	MANE Select	c.529C>A	p.Arg177Ser	missense	Exon 6 of 22	ENSP00000507927.1	Q92674-1
	CENPI	ENST00000372927.5	TSL:5	c.529C>A	p.Arg177Ser	missense	Exon 5 of 21	ENSP00000362018.1	Q92674-1
	CENPI	ENST00000684367.1		c.529C>A	p.Arg177Ser	missense	Exon 7 of 23	ENSP00000507595.1	Q92674-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000822 AC: 9 AN: 1094313 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 4 AN XY: 359999

African (AFR) AF: 0.00 AC: 0 AN: 26339

American (AMR) AF: 0.00 AC: 0 AN: 35129

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19345

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 53878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40429

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3765

European-Non Finnish (NFE) AF: 0.00000953 AC: 8 AN: 839307

Other (OTH) AF: 0.0000218 AC: 1 AN: 45948

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.3
DANN	Benign	0.89
DEOGEN2	Benign	0.034	T
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.11
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.65	N
REVEL	Benign	0.045
Sift	Benign	0.81	T
Sift4G	Benign	0.59	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.54		Loss of methylation at K178 (P = 0.0613)
MVP		0.22
MPC		0.42
ClinPred		0.13	T
GERP RS		1.5
Varity_R		0.12
gMVP		0.070
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775674652; hg19: chrX-100364925;