NM_001040694.2:c.2415G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_001040694.2(INCENP):c.2415G>C(p.Gln805His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,998 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 8 hom. )

Consequence

INCENP
NM_001040694.2 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: -0.916

Publications

4 publications found

Variant links:

Genes affected

INCENP (HGNC:6058): (inner centromere protein) In mammalian cells, 2 broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger,' or transiently interacting, proteins (reviewed by Choo, 1997). The constitutive proteins include CENPA (centromere protein A; MIM 117139), CENPB (MIM 117140), CENPC1 (MIM 117141), and CENPD (MIM 117142). The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle (Earnshaw and Mackay, 1994 [PubMed 8088460]). These include CENPE (MIM 117143); MCAK (MIM 604538); KID (MIM 603213); cytoplasmic dynein (e.g., MIM 600112); CliPs (e.g., MIM 179838); and CENPF/mitosin (MIM 600236). The inner centromere proteins (INCENPs) (Earnshaw and Cooke, 1991 [PubMed 1860899]), the initial members of the passenger protein group, display a broad localization along chromosomes in the early stages of mitosis but gradually become concentrated at centromeres as the cell cycle progresses into mid-metaphase. During telophase, the proteins are located within the midbody in the intercellular bridge, where they are discarded after cytokinesis (Cutts et al., 1999 [PubMed 10369859]).[supplied by OMIM, Mar 2008]

INCENP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP5

Variant 11-62150080-G-C is Pathogenic according to our data. Variant chr11-62150080-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548641.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.010879815). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 381 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INCENP	NM_001040694.2 link	c.2415G>C	p.Gln805His	missense_variant	Exon 18 of 19	ENST00000394818.8	NP_001035784.1	Q9NQS7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INCENP	ENST00000394818.8 link	c.2415G>C	p.Gln805His	missense_variant	Exon 18 of 19	1	NM_001040694.2	ENSP00000378295.3		Q9NQS7-1
INCENP	ENST00000278849.5 link	c.2403G>C	p.Gln801His	missense_variant	Exon 17 of 18	5		ENSP00000278849.4		Q9NQS7-2

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

381

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00278

AC:

699

AN:

251344

AF XY:

0.00286

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0116

Gnomad NFE exome

AF:

0.00321

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00305

AC:

4454

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2185

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00174

AC:

150

AN:

86256

European-Finnish (FIN)

AF:

0.0114

AC:

608

AN:

53324

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00320

AC:

3553

AN:

1111992

Other (OTH)

AF:

0.00179

AC:

108

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

235

471

706

942

1177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00250

AC:

381

AN:

152226

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41536

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00124

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0119

AC:

126

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00316

AC:

215

AN:

68002

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.00262

Hom.:

Bravo

AF:

0.00164

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00278

AC:

337

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00279

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Nephronophthisis

Pathogenic:1

Dec 23, 2015

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

-0.92

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.012

D;D

Sift4G

Benign

0.091

T;T

Polyphen

0.99

D;D

Vest4

0.37

MutPred

0.14

Gain of catalytic residue at Q805 (P = 0.076);.;

MVP

0.33

MPC

0.88

ClinPred

0.042

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.33

Mutation Taster

=99/1

disease causing (ClinVar)

(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