NM_002417.5:c.9649A>G

Variant names:

• chr10-128101314-T-C
• rs8473
• NM_002417.5:c.9649A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002417.5(MKI67):​c.9649A>G​(p.Lys3217Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 1,613,866 control chromosomes in the GnomAD database, including 214,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (19138 hom., cov: 34)
  • Exomes 𝑓: 0.52 (195110 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.513

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.121955E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKI67	NM_002417.5	c.9649A>G	p.Lys3217Glu	missense_variant	Exon 14 of 15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2	c.8569A>G	p.Lys2857Glu	missense_variant	Exon 13 of 14		NP_001139438.1
MKI67	XM_011539818.3	c.8617A>G	p.Lys2873Glu	missense_variant	Exon 11 of 12		XP_011538120.1
MKI67	XM_006717864.4	c.7327A>G	p.Lys2443Glu	missense_variant	Exon 3 of 4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8	c.9649A>G	p.Lys3217Glu	missense_variant	Exon 14 of 15	2	NM_002417.5	ENSP00000357643.3
MKI67	ENST00000368653.7	c.8569A>G	p.Lys2857Glu	missense_variant	Exon 13 of 14	2		ENSP00000357642.3
MKI67	ENST00000464771.1	n.*170A>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75960 AN: 152020 Hom.: 19137 Cov.: 34

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.524

GnomAD3 exomes AF: 0.508 AC: 127625 AN: 251464 Hom.: 32979 AF XY: 0.502 AC XY: 68189 AN XY: 135906

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.407

Gnomad SAS exome AF: 0.418

Gnomad FIN exome AF: 0.478

Gnomad NFE exome AF: 0.525

Gnomad OTH exome AF: 0.525

GnomAD4 exome AF: 0.515 AC: 753278 AN: 1461728 Hom.: 195110 Cov.: 63 AF XY: 0.512 AC XY: 372613 AN XY: 727158

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.595

Gnomad4 ASJ exome AF: 0.576

Gnomad4 EAS exome AF: 0.443

Gnomad4 SAS exome AF: 0.421

Gnomad4 FIN exome AF: 0.486

Gnomad4 NFE exome AF: 0.524

Gnomad4 OTH exome AF: 0.506

GnomAD4 genome AF: 0.499 AC: 75988 AN: 152138 Hom.: 19138 Cov.: 34 AF XY: 0.498 AC XY: 37012 AN XY: 74386

Gnomad4 AFR AF: 0.465

Gnomad4 AMR AF: 0.558

Gnomad4 ASJ AF: 0.573

Gnomad4 EAS AF: 0.402

Gnomad4 SAS AF: 0.406

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.523

Alfa AF: 0.523 Hom.: 46245

Bravo AF: 0.509

TwinsUK AF: 0.518 AC: 1920

ALSPAC AF: 0.537 AC: 2070

ESP6500AA AF: 0.464 AC: 2045

ESP6500EA AF: 0.525 AC: 4511

ExAC AF: 0.501 AC: 60891

Asia WGS AF: 0.433 AC: 1507 AN: 3478

EpiCase AF: 0.526

EpiControl AF: 0.528

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.36
DANN	Benign	0.12
DEOGEN2	Benign	0.0028	.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.0000081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.039
MPC		0.052
ClinPred		0.0049	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.013

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

Publications

LitVar

Other links and lift over

dbSNP: rs8473; hg19: chr10-129899578; COSMIC: COSV64073880; COSMIC: COSV64073880;