Genetic Variant CENPI:p.Asp195Gly (chrX-101109991-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001386188.2(CENPI):c.584A>G(p.Asp195Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000439 in 1,162,523 control chromosomes in the GnomAD database, including 1 homozygotes. There are 20 hemizygotes in GnomAD. In-silico tool predicts 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. D195A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.000033 ( 1 hom. 9 hem. )

Consequence

CENPI
NM_001386188.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.96

Publications

0 publications found

Variant links:

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

CENPI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.09489685).

BS2

High Hemizygotes in GnomAd4 at 11 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CENPI	NM_001386188.2	MANE Select	c.584A>G	p.Asp195Gly	missense	Exon 6 of 22	NP_001373117.1	Q92674-1
CENPI	NM_006733.3		c.584A>G	p.Asp195Gly	missense	Exon 5 of 21	NP_006724.2	Q92674-1
CENPI	NM_001318521.2		c.584A>G	p.Asp195Gly	missense	Exon 6 of 21	NP_001305450.1	A0A8C8KX99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CENPI	ENST00000682095.1	MANE Select	c.584A>G	p.Asp195Gly	missense	Exon 6 of 22	ENSP00000507927.1	Q92674-1
CENPI	ENST00000372927.5	TSL:5	c.584A>G	p.Asp195Gly	missense	Exon 5 of 21	ENSP00000362018.1	Q92674-1
CENPI	ENST00000684367.1		c.584A>G	p.Asp195Gly	missense	Exon 7 of 23	ENSP00000507595.1	Q92674-1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

112072

Hom.:

Cov.:

show subpopulations

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:

0.00246

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000112

AC:

AN:

178694

AF XY:

0.000142

show subpopulations

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:

0.00130

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1050451

Hom.:

Cov.:

AF XY:

0.0000280

AC XY:

AN XY:

321437

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25516

American (AMR)

AF:

0.00

AC:

AN:

34751

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19051

East Asian (EAS)

AF:

0.00

AC:

AN:

30013

South Asian (SAS)

AF:

0.00

AC:

AN:

52388

European-Finnish (FIN)

AF:

0.000851

AC:

AN:

39941

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3251

European-Non Finnish (NFE)

AF:

0.00000125

AC:

AN:

801029

Other (OTH)

AF:

0.00

AC:

AN:

44511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000143

AC:

AN:

112072

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

34208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30870

American (AMR)

AF:

0.00

AC:

AN:

10492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3589

South Asian (SAS)

AF:

0.00

AC:

AN:

2724

European-Finnish (FIN)

AF:

0.00246

AC:

AN:

6088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53234

Other (OTH)

AF:

0.00

AC:

AN:

1505

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000116

Hom.:

ExAC

AF:

0.000148

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.059

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.6

PhyloP100

4.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.24

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.023

Polyphen

0.97

Vest4

0.54

MutPred

0.62

Loss of helix (P = 0.079)

MVP

0.61

MPC

0.98

ClinPred

0.41

GERP RS

5.4

Varity_R

0.58

gMVP

0.36

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over