rs77652527

Positions:

chr7-152252650-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_170606.3(KMT2C):c.1365A>G(p.Ile455Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,613,196 control chromosomes in the GnomAD database, including 1,244 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 0.025 ( 77 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1167 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.0770

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 -19 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=0.0062871873).

BP6

Variant 7-152252650-T-C is Benign according to our data. Variant chr7-152252650-T-C is described in ClinVar as [Benign]. Clinvar id is 134736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152252650-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3815/152324) while in subpopulation NFE AF= 0.0401 (2726/68018). AF 95% confidence interval is 0.0388. There are 77 homozygotes in gnomad4. There are 1743 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3815 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3 linkuse as main transcript	c.1365A>G	p.Ile455Met	missense_variant	10/59	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.1365A>G	p.Ile455Met	missense_variant	10/59	1	NM_170606.3	ENSP00000262189	P2	Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3817

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00704

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0238

AC:

5971

AN:

250670

Hom.:

109

AF XY:

0.0241

AC XY:

3265

AN XY:

135480

show subpopulations

Gnomad AFR exome

AF:

0.00640

Gnomad AMR exome

AF:

0.0170

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00611

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0368

AC:

53792

AN:

1460872

Hom.:

1167

Cov.:

AF XY:

0.0358

AC XY:

26049

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.00598

Gnomad4 AMR exome

AF:

0.0172

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00589

Gnomad4 FIN exome

AF:

0.0245

Gnomad4 NFE exome

AF:

0.0438

Gnomad4 OTH exome

AF:

0.0298

GnomAD4 genome

AF:

0.0250

AC:

3815

AN:

152324

Hom.:

Cov.:

AF XY:

0.0234

AC XY:

1743

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00702

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.0268

Gnomad4 NFE

AF:

0.0401

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0363

Hom.:

170

Bravo

AF:

0.0241

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0434

AC:

373

ExAC

AF:

0.0230

AC:

2790

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0361

EpiControl

AF:

0.0382

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

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	Jan 29, 2024	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.095

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.85

.;T

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.35

N;N

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.89

N;N

REVEL

Benign

0.20

Sift

Benign

0.15

T;T

Polyphen

0.0040

B;B

Vest4

0.17

MPC

0.039

ClinPred

0.0034

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.060

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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