chrX-101109548-C-G

Variant names:

• chrX-101109548-C-G
• rs769851684
• NM_001386188.2:c.440C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001386188.2(CENPI):​c.440C>G​(p.Ala147Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,207,137 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 6 hem.)
• Consequence: CENPI NM_001386188.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 6 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.440C>G	p.Ala147Gly	missense	Exon 5 of 22	NP_001373117.1	Q92674-1
	CENPI	NM_006733.3		c.440C>G	p.Ala147Gly	missense	Exon 4 of 21	NP_006724.2	Q92674-1
	CENPI	NM_001318521.2		c.440C>G	p.Ala147Gly	missense	Exon 5 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.440C>G	p.Ala147Gly	missense	Exon 5 of 22	ENSP00000507927.1	Q92674-1
	CENPI	ENST00000372927.5	TSL:5	c.440C>G	p.Ala147Gly	missense	Exon 4 of 21	ENSP00000362018.1	Q92674-1
	CENPI	ENST00000684367.1		c.440C>G	p.Ala147Gly	missense	Exon 6 of 23	ENSP00000507595.1	Q92674-1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112321 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183191 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 13 AN: 1094816 Hom.: 0 Cov.: 28 AF XY: 0.0000167 AC XY: 6 AN XY: 360232

African (AFR) AF: 0.00 AC: 0 AN: 26337

American (AMR) AF: 0.00 AC: 0 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19358

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54055

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4125

European-Non Finnish (NFE) AF: 0.0000155 AC: 13 AN: 839058

Other (OTH) AF: 0.00 AC: 0 AN: 45993

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112321 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34469

African (AFR) AF: 0.00 AC: 0 AN: 30972

American (AMR) AF: 0.00 AC: 0 AN: 10566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2763

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53286

Other (OTH) AF: 0.00 AC: 0 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

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	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Benign	0.097	T
Sift4G	Benign	0.12	T
Polyphen		0.71	P
Vest4		0.58
MutPred		0.58		Gain of sheet (P = 0.0344)
MVP		0.58
MPC		1.1
ClinPred		0.74	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.53
gMVP		0.42
Mutation Taster		=98/2	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: rs769851684; hg19: chrX-100364537;