rs2240

Variant names:

• chr10-128109280-G-C
• rs2240
• NM_002417.5:c.2560C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002417.5(MKI67):​c.2560C>G​(p.Leu854Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 1,613,934 control chromosomes in the GnomAD database, including 28,295 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (3905 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24390 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 28 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040837824).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5	c.2560C>G	p.Leu854Val	missense_variant	Exon 13 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.1480C>G	p.Leu494Val	missense_variant	Exon 12 of 14		NP_001139438.1
MKI67	XM_011539818.3	c.1528C>G	p.Leu510Val	missense_variant	Exon 10 of 12		XP_011538120.1
MKI67	XM_006717864.4	c.238C>G	p.Leu80Val	missense_variant	Exon 2 of 4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.2560C>G	p.Leu854Val	missense_variant	Exon 13 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.1480C>G	p.Leu494Val	missense_variant	Exon 12 of 14	2		ENSP00000357642.3

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32912 AN: 151968 Hom.: 3906 Cov.: 32

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.190 AC: 47729 AN: 251292 AF XY: 0.183

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.206

Gnomad EAS exome AF: 0.286

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.180 AC: 262436 AN: 1461848 Hom.: 24390 Cov.: 46 AF XY: 0.178 AC XY: 129084 AN XY: 727220

African (AFR) AF: 0.314 AC: 10510 AN: 33478

American (AMR) AF: 0.224 AC: 10030 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5335 AN: 26132

East Asian (EAS) AF: 0.275 AC: 10933 AN: 39692

South Asian (SAS) AF: 0.141 AC: 12152 AN: 86252

European-Finnish (FIN) AF: 0.128 AC: 6825 AN: 53418

Middle Eastern (MID) AF: 0.165 AC: 953 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194322 AN: 1111990

Other (OTH) AF: 0.188 AC: 11376 AN: 60394

GnomAD4 genome AF: 0.217 AC: 32928 AN: 152086 Hom.: 3905 Cov.: 32 AF XY: 0.215 AC XY: 15958 AN XY: 74346

African (AFR) AF: 0.315 AC: 13046 AN: 41466

American (AMR) AF: 0.226 AC: 3448 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 692 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1385 AN: 5160

South Asian (SAS) AF: 0.138 AC: 663 AN: 4818

European-Finnish (FIN) AF: 0.125 AC: 1328 AN: 10586

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11628 AN: 67994

Other (OTH) AF: 0.211 AC: 445 AN: 2108

Alfa AF: 0.190 Hom.: 935

Bravo AF: 0.228

TwinsUK AF: 0.173 AC: 640

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.309 AC: 1363

ESP6500EA AF: 0.174 AC: 1493

ExAC AF: 0.188 AC: 22831

Asia WGS AF: 0.243 AC: 848 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.173

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.019
DANN	Benign	0.057
DEOGEN2	Benign	0.0035	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.16	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.55	.;N
PhyloP100		-1.8
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.91	N;N
REVEL	Benign	0.012
Sift	Benign	1.0	T;T
Sift4G	Benign	0.85	T;T
Polyphen		0.0	B;B
Vest4		0.011
MPC		0.042
ClinPred		0.00030	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.015
gMVP		0.024
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2240; hg19: chr10-129907544; COSMIC: COSV64073334; COSMIC: COSV64073334;