10-128099234-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002417.5(MKI67):​c.9727A>C​(p.Lys3243Gln) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

MKI67
NM_002417.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.58
Variant links:
Genes affected
MKI67 (HGNC:7107): (marker of proliferation Ki-67) Enables protein C-terminus binding activity. Involved in regulation of chromosome segregation and regulation of mitotic nuclear division. Located in chromosome; nuclear body; and nucleolus. Colocalizes with condensed chromosome. Implicated in Crohn's disease; breast cancer; human immunodeficiency virus infectious disease; and pancreatic cancer. Biomarker of several diseases, including Barrett's esophagus; autoimmune disease of musculoskeletal system (multiple); endocrine gland cancer (multiple); gastrointestinal system cancer (multiple); and interstitial cystitis. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.25041422).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MKI67NM_002417.5 linkuse as main transcriptc.9727A>C p.Lys3243Gln missense_variant 15/15 ENST00000368654.8 NP_002408.3
MKI67NM_001145966.2 linkuse as main transcriptc.8647A>C p.Lys2883Gln missense_variant 14/14 NP_001139438.1
MKI67XM_011539818.3 linkuse as main transcriptc.8695A>C p.Lys2899Gln missense_variant 12/12 XP_011538120.1
MKI67XM_006717864.4 linkuse as main transcriptc.7405A>C p.Lys2469Gln missense_variant 4/4 XP_006717927.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MKI67ENST00000368654.8 linkuse as main transcriptc.9727A>C p.Lys3243Gln missense_variant 15/152 NM_002417.5 ENSP00000357643 P2P46013-1
MKI67ENST00000368653.7 linkuse as main transcriptc.8647A>C p.Lys2883Gln missense_variant 14/142 ENSP00000357642 A2P46013-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

MKI67-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 15, 2023The MKI67 c.9727A>C variant is predicted to result in the amino acid substitution p.Lys3243Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.34
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.016
.;T
Eigen
Uncertain
0.23
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.56
T;T
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.97
.;L
MutationTaster
Benign
0.98
N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.053
Sift
Uncertain
0.029
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.24
MutPred
0.34
.;Loss of methylation at K3243 (P = 0.0039);
MVP
0.30
MPC
0.29
ClinPred
0.87
D
GERP RS
4.0
Varity_R
0.098
gMVP
0.043

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-129897498; API