rs142835638

Positions:

chr7-152163145-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_170606.3(KMT2C):c.10432C>G(p.Gln3478Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,176 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 26 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 9.31

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060453415).

BP6

Variant 7-152163145-G-C is Benign according to our data. Variant chr7-152163145-G-C is described in ClinVar as [Benign]. Clinvar id is 134788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152163145-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3 linkuse as main transcript	c.10432C>G	p.Gln3478Glu	missense_variant	43/59	ENST00000262189.11	NP_733751.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11 linkuse as main transcript	c.10432C>G	p.Gln3478Glu	missense_variant	43/59	1	NM_170606.3	ENSP00000262189	P2	Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00308

AC:

468

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00395

AC:

992

AN:

251446

Hom.:

AF XY:

0.00422

AC XY:

574

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000752

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00634

Gnomad FIN exome

AF:

0.00346

Gnomad NFE exome

AF:

0.00571

Gnomad OTH exome

AF:

0.00424

GnomAD4 exome

AF:

0.00444

AC:

6494

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00455

AC XY:

3307

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00119

Gnomad4 ASJ exome

AF:

0.000803

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00661

Gnomad4 FIN exome

AF:

0.00447

Gnomad4 NFE exome

AF:

0.00484

Gnomad4 OTH exome

AF:

0.00328

GnomAD4 genome

AF:

0.00308

AC:

469

AN:

152296

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00377

Gnomad4 NFE

AF:

0.00462

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00363

Hom.:

Bravo

AF:

0.00300

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00451

AC:

547

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.00305

EpiControl

AF:

0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KMT2C: BS1, BS2 -

not specified

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 15, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

KMT2C-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.30

T;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.0060

T;T;T

MetaSVM

Uncertain

0.089

MutationAssessor

Uncertain

2.4

M;M;.

MutationTaster

Benign

0.89

D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Uncertain

0.36

Sift

Uncertain

0.0080

D;D;D

Sift4G

Benign

0.37

.;.;T

Polyphen

0.96

D;D;.

Vest4

0.45

MVP

0.63

MPC

0.23

ClinPred

0.033

GERP RS

5.3

Varity_R

0.24

gMVP

0.37

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

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