X-101102403-G-A

Variant names:

• chrX-101102403-G-A
• NM_001386188.2:c.356G>A

Variant summary

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

The NM_001386188.2(CENPI):​c.356G>A​(p.Gly119Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,059,716 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G119G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09
• 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: 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_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.356G>A	p.Gly119Asp	missense	Exon 4 of 22	NP_001373117.1	Q92674-1
	CENPI	NM_006733.3		c.356G>A	p.Gly119Asp	missense	Exon 3 of 21	NP_006724.2	Q92674-1
	CENPI	NM_001318521.2		c.356G>A	p.Gly119Asp	missense	Exon 4 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.356G>A	p.Gly119Asp	missense	Exon 4 of 22	ENSP00000507927.1	Q92674-1
	CENPI	ENST00000372927.5	TSL:5	c.356G>A	p.Gly119Asp	missense	Exon 3 of 21	ENSP00000362018.1	Q92674-1
	CENPI	ENST00000684367.1		c.356G>A	p.Gly119Asp	missense	Exon 5 of 23	ENSP00000507595.1	Q92674-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000283 AC: 3 AN: 1059716 Hom.: 0 Cov.: 25 AF XY: 0.00000299 AC XY: 1 AN XY: 334052

African (AFR) AF: 0.00 AC: 0 AN: 25070

American (AMR) AF: 0.0000639 AC: 2 AN: 31281

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18262

East Asian (EAS) AF: 0.00 AC: 0 AN: 29026

South Asian (SAS) AF: 0.00 AC: 0 AN: 48093

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3836

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 820621

Other (OTH) AF: 0.00 AC: 0 AN: 44283

GnomAD4 genome Cov.: 22

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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0085	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.23
Sift	Uncertain	0.017	D
Sift4G	Benign	0.098	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.58		Loss of catalytic residue at G119 (P = 0.0172)
MVP		0.51
MPC		1.3
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.35
Mutation Taster		=83/17	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

hg19: chrX-100357392;