10-128103682-T-G

Variant names:

• chr10-128103682-T-G
• rs1050767
• NM_002417.5:c.8158A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002417.5(MKI67):​c.8158A>C​(p.Thr2720Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,613,946 control chromosomes in the GnomAD database, including 27,336 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2720K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (3449 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23887 hom.)
• Consequence: MKI67 NM_002417.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.242
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006007552).
• BP6: Variant 10-128103682-T-G is Benign according to our data. Variant chr10-128103682-T-G is described in ClinVar as Benign. ClinVar VariationId is 1274348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.277 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.8158A>C	p.Thr2720Pro	missense	Exon 13 of 15	NP_002408.3
	MKI67	NM_001145966.2		c.7078A>C	p.Thr2360Pro	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.8158A>C	p.Thr2720Pro	missense	Exon 13 of 15	ENSP00000357643.3	P46013-1
	MKI67	ENST00000935442.1		c.8152A>C	p.Thr2718Pro	missense	Exon 13 of 15	ENSP00000605501.1
	MKI67	ENST00000368653.7	TSL:2	c.7078A>C	p.Thr2360Pro	missense	Exon 12 of 14	ENSP00000357642.3	P46013-2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31376 AN: 151946 Hom.: 3450 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.187 AC: 47095 AN: 251350 AF XY: 0.181

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.221

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: 0.167

GnomAD4 exome AF: 0.178 AC: 260571 AN: 1461882 Hom.: 23887 Cov.: 75 AF XY: 0.176 AC XY: 128261 AN XY: 727240

African (AFR) AF: 0.276 AC: 9257 AN: 33480

American (AMR) AF: 0.222 AC: 9935 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5337 AN: 26136

East Asian (EAS) AF: 0.275 AC: 10923 AN: 39700

South Asian (SAS) AF: 0.141 AC: 12138 AN: 86258

European-Finnish (FIN) AF: 0.128 AC: 6814 AN: 53416

Middle Eastern (MID) AF: 0.160 AC: 925 AN: 5768

European-Non Finnish (NFE) AF: 0.175 AC: 194107 AN: 1112004

Other (OTH) AF: 0.184 AC: 11135 AN: 60396

GnomAD4 genome AF: 0.206 AC: 31384 AN: 152064 Hom.: 3449 Cov.: 32 AF XY: 0.205 AC XY: 15264 AN XY: 74350

African (AFR) AF: 0.281 AC: 11638 AN: 41436

American (AMR) AF: 0.221 AC: 3377 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1374 AN: 5152

South Asian (SAS) AF: 0.137 AC: 660 AN: 4820

European-Finnish (FIN) AF: 0.125 AC: 1322 AN: 10600

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.171 AC: 11607 AN: 67994

Other (OTH) AF: 0.201 AC: 423 AN: 2102

Alfa AF: 0.187 Hom.: 9326

Bravo AF: 0.216

TwinsUK AF: 0.172 AC: 638

ALSPAC AF: 0.181 AC: 698

ESP6500AA AF: 0.270 AC: 1190

ESP6500EA AF: 0.173 AC: 1489

ExAC AF: 0.185 AC: 22442

Asia WGS AF: 0.239 AC: 834 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.0
DANN	Benign	0.84
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.24
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.017
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.21
MPC		0.30
ClinPred		0.0095	T
GERP RS		-0.38
Varity_R		0.23
gMVP		0.034
Mutation Taster		=99/1	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: rs1050767; hg19: chr10-129901946; COSMIC: COSV64073325; COSMIC: COSV64073325;