chr10-128103237-G-C

Variant names:

• chr10-128103237-G-C
• rs2071496
• NM_002417.5:c.8603C>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.8603C>G​(p.Thr2868Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.238 in 1,614,008 control chromosomes in the GnomAD database, including 47,225 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 0.20 (3709 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43516 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.814
• Publications: 23 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=0.00476712).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

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.8603C>G	p.Thr2868Ser	missense	Exon 13 of 15	NP_002408.3
	MKI67	NM_001145966.2		c.7523C>G	p.Thr2508Ser	missense	Exon 12 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.8603C>G	p.Thr2868Ser	missense	Exon 13 of 15	ENSP00000357643.3	P46013-1
	MKI67	ENST00000935442.1		c.8597C>G	p.Thr2866Ser	missense	Exon 13 of 15	ENSP00000605501.1
	MKI67	ENST00000368653.7	TSL:2	c.7523C>G	p.Thr2508Ser	missense	Exon 12 of 14	ENSP00000357642.3	P46013-2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31162 AN: 152010 Hom.: 3702 Cov.: 32

Gnomad AFR AF: 0.0939

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.239

GnomAD2 exomes AF: 0.242 AC: 60883 AN: 251420 AF XY: 0.241

Gnomad AFR exome AF: 0.0886

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.241 AC: 352262 AN: 1461880 Hom.: 43516 Cov.: 81 AF XY: 0.241 AC XY: 174984 AN XY: 727244

African (AFR) AF: 0.0865 AC: 2895 AN: 33480

American (AMR) AF: 0.319 AC: 14259 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7781 AN: 26136

East Asian (EAS) AF: 0.160 AC: 6353 AN: 39700

South Asian (SAS) AF: 0.210 AC: 18142 AN: 86258

European-Finnish (FIN) AF: 0.291 AC: 15534 AN: 53410

Middle Eastern (MID) AF: 0.268 AC: 1546 AN: 5768

European-Non Finnish (NFE) AF: 0.244 AC: 271681 AN: 1112008

Other (OTH) AF: 0.233 AC: 14071 AN: 60396

GnomAD4 genome AF: 0.205 AC: 31170 AN: 152128 Hom.: 3709 Cov.: 32 AF XY: 0.208 AC XY: 15434 AN XY: 74364

African (AFR) AF: 0.0936 AC: 3887 AN: 41512

American (AMR) AF: 0.273 AC: 4168 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3470

East Asian (EAS) AF: 0.128 AC: 663 AN: 5168

South Asian (SAS) AF: 0.203 AC: 980 AN: 4816

European-Finnish (FIN) AF: 0.293 AC: 3096 AN: 10554

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16463 AN: 67996

Other (OTH) AF: 0.238 AC: 504 AN: 2114

Alfa AF: 0.240 Hom.: 1502

Bravo AF: 0.203

TwinsUK AF: 0.239 AC: 888

ALSPAC AF: 0.244 AC: 942

ESP6500AA AF: 0.0942 AC: 415

ESP6500EA AF: 0.248 AC: 2130

ExAC AF: 0.236 AC: 28632

Asia WGS AF: 0.152 AC: 528 AN: 3478

EpiCase AF: 0.251

EpiControl AF: 0.259

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.74
DEOGEN2	Benign	0.0080	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.81
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.028
Sift	Benign	0.19	T
Sift4G	Benign	0.40	T
Polyphen		0.98	D
Vest4		0.075
MutPred		0.31		Loss of loop (P = 0.0288)
MPC		0.15
ClinPred		0.010	T
GERP RS		-2.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.054
gMVP		0.035
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: rs2071496; hg19: chr10-129901501; COSMIC: COSV64072613; COSMIC: COSV64072613;