rs28522267

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PP2PP3BP4_StrongBP6_Very_Strong

The NM_170606.3(KMT2C):c.2963G>T(p.Cys988Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 0 hom., cov: 42)

Exomes 𝑓: 0.49 ( 39 hom. )

Failed GnomAD Quality Control

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.90

Variant links:

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

KMT2C links:

KMT2C (HGNC:):

KMT2C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2C. . Gene score misZ 2.1357 (greater than the threshold 3.09). Trascript score misZ 4.2875 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Kleefstra syndrome 2.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.008740902).

BP6

Variant 7-152229936-C-A is Benign according to our data. Variant chr7-152229936-C-A is described in ClinVar as [Benign]. Clinvar id is 403019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3 linkuse as main transcript	c.2963G>T	p.Cys988Phe	missense_variant	18/59	ENST00000262189.11	NP_733751.2	Q8NEZ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11 linkuse as main transcript	c.2963G>T	p.Cys988Phe	missense_variant	18/59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

46723

AN:

108170

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.486

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.343

Gnomad SAS

AF:

0.366

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.404

GnomAD3 exomes

AF:

0.198

AC:

27538

AN:

139298

Hom.:

AF XY:

0.177

AC XY:

13344

AN XY:

75550

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.229

Gnomad ASJ exome

AF:

0.170

Gnomad EAS exome

AF:

0.235

Gnomad SAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.303

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.488

AC:

634391

AN:

1300290

Hom.:

Cov.:

AF XY:

0.488

AC XY:

315602

AN XY:

647150

show subpopulations

Gnomad4 AFR exome

AF:

0.468

Gnomad4 AMR exome

AF:

0.485

Gnomad4 ASJ exome

AF:

0.468

Gnomad4 EAS exome

AF:

0.469

Gnomad4 SAS exome

AF:

0.492

Gnomad4 FIN exome

AF:

0.479

Gnomad4 NFE exome

AF:

0.490

Gnomad4 OTH exome

AF:

0.478

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.432

AC:

46735

AN:

108214

Hom.:

Cov.:

AF XY:

0.431

AC XY:

23365

AN XY:

54184

show subpopulations

Gnomad4 AFR

AF:

0.405

Gnomad4 AMR

AF:

0.404

Gnomad4 ASJ

AF:

0.457

Gnomad4 EAS

AF:

0.343

Gnomad4 SAS

AF:

0.368

Gnomad4 FIN

AF:

0.421

Gnomad4 NFE

AF:

0.464

Gnomad4 OTH

AF:

0.403

Alfa

AF:

0.361

Hom.:

ExAC

AF:

0.105

AC:

12517

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

MetaRNN

Benign

0.0087

T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-9.0

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.84

MPC

2.9

ClinPred

0.055

GERP RS

4.7

Varity_R

0.95

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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