Genetic Variant MKI67:p.Arg3095Gly (chr10-128101680-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002417.5(MKI67):c.9283C>G(p.Arg3095Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R3095C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MKI67
NM_002417.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.348

Publications

0 publications found

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]

MKI67 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09382802).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002417.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKI67	NM_002417.5	MANE Select	c.9283C>G	p.Arg3095Gly	missense	Exon 14 of 15	NP_002408.3
	MKI67	NM_001145966.2		c.8203C>G	p.Arg2735Gly	missense	Exon 13 of 14	NP_001139438.1	P46013-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MKI67	ENST00000368654.8	TSL:2 MANE Select	c.9283C>G	p.Arg3095Gly	missense	Exon 14 of 15	ENSP00000357643.3	P46013-1
MKI67	ENST00000935442.1		c.9277C>G	p.Arg3093Gly	missense	Exon 14 of 15	ENSP00000605501.1
MKI67	ENST00000368653.7	TSL:2	c.8203C>G	p.Arg2735Gly	missense	Exon 13 of 14	ENSP00000357642.3	P46013-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1450194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32518

American (AMR)

AF:

0.00

AC:

AN:

42342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25680

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

83636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107706

Other (OTH)

AF:

0.00

AC:

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0097

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.57

M_CAP

Benign

0.0078

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.81

PhyloP100

0.35

PrimateAI

Benign

0.21

PROVEAN

Benign

-2.0

REVEL

Benign

0.065

Sift

Benign

0.48

Sift4G

Benign

0.16

Polyphen

0.98

Vest4

0.34

MutPred

0.32

Gain of relative solvent accessibility (P = 0.0166)

MVP

0.32

MPC

0.26

ClinPred

0.48

GERP RS

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.066

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over