Genetic Variant NM_001040694.2:c.1188T>G (chr11-62138902-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040694.2(INCENP):c.1188T>G(p.Asn396Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. N396S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

INCENP
NM_001040694.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.62

Publications

26 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048291713).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040694.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INCENP	NM_001040694.2	MANE Select	c.1188T>G	p.Asn396Lys	missense	Exon 7 of 19	NP_001035784.1
	INCENP	NM_020238.3		c.1188T>G	p.Asn396Lys	missense	Exon 7 of 18	NP_064623.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
INCENP	ENST00000394818.8	TSL:1 MANE Select	c.1188T>G	p.Asn396Lys	missense	Exon 7 of 19	ENSP00000378295.3
INCENP	ENST00000278849.5	TSL:5	c.1188T>G	p.Asn396Lys	missense	Exon 7 of 18	ENSP00000278849.4
INCENP	ENST00000528375.1	TSL:3	n.157T>G		non_coding_transcript_exon	Exon 4 of 8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726988

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111446

Other (OTH)

AF:

0.00

AC:

AN:

60376

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

97026

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.011

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.044

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.38

M_CAP

Benign

0.0054

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-1.6

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.91

REVEL

Benign

0.025

Sift

Benign

0.38

Sift4G

Benign

0.93

Polyphen

0.0020

Vest4

0.031

MutPred

0.13

Gain of ubiquitination at N396 (P = 0.0018)

MVP

0.48

MPC

0.30

ClinPred

0.064

GERP RS

-3.0

Varity_R

0.024

gMVP

0.080

Mutation Taster

=96/4

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over