10-128101680-G-A

Variant names:

• chr10-128101680-G-A
• rs754001305
• NM_002417.5:c.9283C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002417.5(MKI67):​c.9283C>T​(p.Arg3095Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000761 in 1,602,434 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.348
• Publications: 2 publications found

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]

ACMG classification

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=0.04572466).

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>T	p.Arg3095Cys	missense	Exon 14 of 15	NP_002408.3
	MKI67	NM_001145966.2		c.8203C>T	p.Arg2735Cys	missense	Exon 13 of 14	NP_001139438.1	P46013-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKI67	ENST00000368654.8	TSL:2 MANE Select	c.9283C>T	p.Arg3095Cys	missense	Exon 14 of 15	ENSP00000357643.3	P46013-1
	MKI67	ENST00000935442.1		c.9277C>T	p.Arg3093Cys	missense	Exon 14 of 15	ENSP00000605501.1
	MKI67	ENST00000368653.7	TSL:2	c.8203C>T	p.Arg2735Cys	missense	Exon 13 of 14	ENSP00000357642.3	P46013-2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152122 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000792 AC: 19 AN: 239952 AF XY: 0.0000922

Gnomad AFR exome AF: 0.0000654

Gnomad AMR exome AF: 0.0000622

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.0000745 AC: 108 AN: 1450194 Hom.: 0 Cov.: 33 AF XY: 0.0000722 AC XY: 52 AN XY: 720504

African (AFR) AF: 0.0000308 AC: 1 AN: 32518

American (AMR) AF: 0.0000236 AC: 1 AN: 42342

Ashkenazi Jewish (ASJ) AF: 0.0000779 AC: 2 AN: 25680

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 83636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53154

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5706

European-Non Finnish (NFE) AF: 0.0000794 AC: 88 AN: 1107706

Other (OTH) AF: 0.000134 AC: 8 AN: 59822

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152240 Hom.: 1 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000742 AC: 9

EpiCase AF: 0.0000546

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.35
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.026
Sift	Benign	0.20	T
Sift4G	Uncertain	0.055	T
Polyphen		0.36	B
Vest4		0.35
MutPred		0.40		Loss of MoRF binding (P = 0.0083)
MVP		0.31
MPC		0.32
ClinPred		0.062	T
GERP RS		0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.054
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs754001305; hg19: chr10-129899944; COSMIC: COSV64076880;