7-152177496-G-C

Position:

chr7-152177496-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.7957C>G(p.Leu2653Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00707 in 1,614,184 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0072 ( 55 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4O:1

Conservation

PhyloP100: 0.710

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 -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=0.0022338629).

BP6

Variant 7-152177496-G-C is Benign according to our data. Variant chr7-152177496-G-C is described in ClinVar as [Benign]. Clinvar id is 134776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152177496-G-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 938 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3 linkuse as main transcript	c.7957C>G	p.Leu2653Val	missense_variant	38/59	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.7957C>G	p.Leu2653Val	missense_variant	38/59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00616

AC:

937

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00883

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00667

AC:

1677

AN:

251292

Hom.:

AF XY:

0.00656

AC XY:

891

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.00879

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00716

AC:

10467

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

5189

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00138

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00381

Gnomad4 FIN exome

AF:

0.0205

Gnomad4 NFE exome

AF:

0.00769

Gnomad4 OTH exome

AF:

0.00535

GnomAD4 genome

AF:

0.00616

AC:

938

AN:

152304

Hom.:

Cov.:

AF XY:

0.00634

AC XY:

472

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0192

Gnomad4 NFE

AF:

0.00883

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00787

Hom.:

Bravo

AF:

0.00464

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00849

AC:

ExAC

AF:

0.00684

AC:

831

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00788

ClinVar

Significance: Benign

Submissions summary: Benign:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KMT2C: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

KMT2C-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2022

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). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

2.7

DANN

Benign

0.12

DEOGEN2

Benign

0.051

T;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.19

Sift

Benign

0.69

T;T

Polyphen

0.0

B;B

Vest4

0.041

MVP

0.32

MPC

0.079

ClinPred

0.00014

GERP RS

-0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.019

gMVP

0.14

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