10-128101259-T-C

Position:

chr10-128101259-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002417.5(MKI67):c.9704A>G(p.Lys3235Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,607,284 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

MKI67
NM_002417.5 missense, splice_region

Scores

Splicing: ADA: 0.2164

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.557

Variant links:

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]

MKI67 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018297732).

BP6

Variant 10-128101259-T-C is Benign according to our data. Variant chr10-128101259-T-C is described in ClinVar as [Benign]. Clinvar id is 780919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1666/152350) while in subpopulation AFR AF= 0.0381 (1585/41564). AF 95% confidence interval is 0.0366. There are 32 homozygotes in gnomad4. There are 796 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MKI67	NM_002417.5 linkuse as main transcript	c.9704A>G	p.Lys3235Arg	missense_variant, splice_region_variant	14/15	ENST00000368654.8	NP_002408.3
MKI67	NM_001145966.2 linkuse as main transcript	c.8624A>G	p.Lys2875Arg	missense_variant, splice_region_variant	13/14		NP_001139438.1
MKI67	XM_011539818.3 linkuse as main transcript	c.8672A>G	p.Lys2891Arg	missense_variant, splice_region_variant	11/12		XP_011538120.1
MKI67	XM_006717864.4 linkuse as main transcript	c.7382A>G	p.Lys2461Arg	missense_variant, splice_region_variant	3/4		XP_006717927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKI67	ENST00000368654.8 linkuse as main transcript	c.9704A>G	p.Lys3235Arg	missense_variant, splice_region_variant	14/15	2	NM_002417.5	ENSP00000357643	P2	P46013-1
MKI67	ENST00000368653.7 linkuse as main transcript	c.8624A>G	p.Lys2875Arg	missense_variant, splice_region_variant	13/14	2		ENSP00000357642	A2	P46013-2

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1661

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0381

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00286

AC:

716

AN:

250158

Hom.:

AF XY:

0.00197

AC XY:

266

AN XY:

135124

show subpopulations

Gnomad AFR exome

AF:

0.0403

Gnomad AMR exome

AF:

0.000958

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000821

GnomAD4 exome

AF:

0.00111

AC:

1619

AN:

1454934

Hom.:

Cov.:

AF XY:

0.000944

AC XY:

682

AN XY:

722212

show subpopulations

Gnomad4 AFR exome

AF:

0.0394

Gnomad4 AMR exome

AF:

0.00135

Gnomad4 ASJ exome

AF:

0.000883

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000551

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.0109

AC:

1666

AN:

152350

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

796

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0381

Gnomad4 AMR

AF:

0.00359

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00268

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0379

AC:

167

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00358

AC:

434

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.97

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.034

Sift

Benign

0.049

D;D

Sift4G

Uncertain

0.059

T;T

Polyphen

0.24

B;B

Vest4

0.13

MVP

0.15

MPC

0.093

ClinPred

0.0070

GERP RS

0.72

Varity_R

0.026

gMVP

0.027

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.22

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over