Variant 7-152222013-C-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_170606.3(KMT2C):c.3487G>C(p.Val1163Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00052 in 1,603,260 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1163A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 3 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 3.67

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:

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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=0.009125531).

BP6

Variant 7-152222013-C-G is Benign according to our data. Variant chr7-152222013-C-G is described in ClinVar as [Benign]. Clinvar id is 134746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 414 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3 linkuse as main transcript	c.3487G>C	p.Val1163Leu	missense_variant	22/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11 linkuse as main transcript	c.3487G>C	p.Val1163Leu	missense_variant	22/59	1	NM_170606.3	P2	Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

413

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000749

AC:

182

AN:

242924

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

131506

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000180

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000289

AC:

420

AN:

1451180

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

186

AN XY:

721464

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.000162

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000813

Gnomad4 OTH exome

AF:

0.000583

GnomAD4 genome

AF:

0.00272

AC:

414

AN:

152080

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00967

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.00314

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.000868

AC:

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	KMT2C: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

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

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

0.089

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

.;T

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.11

N;N

MutationTaster

Benign

0.81

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.22

Sift

Benign

0.21

T;T

Polyphen

0.43

B;B

Vest4

0.24

MutPred

0.20

Loss of methylation at K1162 (P = 0.0464);Loss of methylation at K1162 (P = 0.0464);

MVP

0.71

MPC

1.2

ClinPred

0.0084

GERP RS

5.6

Varity_R

0.19

gMVP

0.38

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