chrX-101127186-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001386188.2(CENPI):c.826G>A(p.Val276Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000997 in 1,189,898 control chromosomes in the GnomAD database, including 6 homozygotes. There are 342 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., 161 hem., cov: 23)

Exomes 𝑓: 0.00058 ( 2 hom. 181 hem. )

Consequence

CENPI
NM_001386188.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0820

Publications

1 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006650746).

BP6

Variant X-101127186-G-A is Benign according to our data. Variant chrX-101127186-G-A is described in ClinVar as Benign. ClinVar VariationId is 734919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00497 (556/111812) while in subpopulation AFR AF = 0.0164 (505/30802). AF 95% confidence interval is 0.0152. There are 4 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPI	NM_001386188.2 link	c.826G>A	p.Val276Met	missense_variant	Exon 10 of 22	ENST00000682095.1	NP_001373117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPI	ENST00000682095.1 link	c.826G>A	p.Val276Met	missense_variant	Exon 10 of 22		NM_001386188.2	ENSP00000507927.1		Q92674-1

Frequencies

GnomAD3 genomes

AF:

0.00497

AC:

555

AN:

111759

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00411

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000278

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00847

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00198

GnomAD2 exomes

AF:

0.00153

AC:

265

AN:

172702

AF XY:

0.00106

show subpopulations

Gnomad AFR exome

AF:

0.0179

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000782

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000962

GnomAD4 exome

AF:

0.000584

AC:

630

AN:

1078086

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

181

AN XY:

347744

show subpopulations

African (AFR)

AF:

0.0174

AC:

451

AN:

25857

American (AMR)

AF:

0.00124

AC:

AN:

33894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18913

East Asian (EAS)

AF:

0.0000334

AC:

AN:

29909

South Asian (SAS)

AF:

0.0000603

AC:

AN:

49789

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39986

Middle Eastern (MID)

AF:

0.00199

AC:

AN:

3022

European-Non Finnish (NFE)

AF:

0.0000722

AC:

AN:

831532

Other (OTH)

AF:

0.00148

AC:

AN:

45184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00497

AC:

556

AN:

111812

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

161

AN XY:

34034

show subpopulations

African (AFR)

AF:

0.0164

AC:

505

AN:

30802

American (AMR)

AF:

0.00411

AC:

AN:

10473

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.000279

AC:

AN:

3590

South Asian (SAS)

AF:

0.00

AC:

AN:

2690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5997

Middle Eastern (MID)

AF:

0.00465

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53194

Other (OTH)

AF:

0.00196

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00180

Hom.:

Bravo

AF:

0.00617

ESP6500AA

AF:

0.0151

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00169

AC:

205

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.2

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;T;T

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.66

T;.;T

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L;L

PhyloP100

0.082

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.036

Sift

Benign

0.038

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.24

.;B;B

Vest4

0.25

MVP

0.17

MPC

0.51

ClinPred

0.013

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.079

gMVP

0.64

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over