7-152180042-G-T

Position:

chr7-152180042-G-T

Variant summary

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

The NM_170606.3(KMT2C):c.7234C>A(p.Pro2412Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,120 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.019 ( 34 hom., cov: 31)

Exomes 𝑓: 0.025 ( 575 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.142

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 -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=0.0026199222).

BP6

Variant 7-152180042-G-T is Benign according to our data. Variant chr7-152180042-G-T is described in ClinVar as [Benign]. Clinvar id is 134768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.019 (2900/152258) while in subpopulation NFE AF= 0.0294 (1997/68028). AF 95% confidence interval is 0.0283. There are 34 homozygotes in gnomad4. There are 1344 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2900 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3 linkuse as main transcript	c.7234C>A	p.Pro2412Thr	missense_variant	37/59	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.7234C>A	p.Pro2412Thr	missense_variant	37/59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2900

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00526

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0294

Gnomad OTH

AF:

0.0267

GnomAD3 exomes

AF:

0.0185

AC:

4646

AN:

251466

Hom.:

AF XY:

0.0188

AC XY:

2561

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00980

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00336

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.0306

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0252

AC:

36781

AN:

1461862

Hom.:

575

Cov.:

AF XY:

0.0246

AC XY:

17896

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00436

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.0202

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00337

Gnomad4 FIN exome

AF:

0.0172

Gnomad4 NFE exome

AF:

0.0296

Gnomad4 OTH exome

AF:

0.0227

GnomAD4 genome

AF:

0.0190

AC:

2900

AN:

152258

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1344

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00527

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.0208

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.0174

Gnomad4 NFE

AF:

0.0294

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.0263

Hom.:

110

Bravo

AF:

0.0185

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0292

AC:

251

ExAC

AF:

0.0191

AC:

2320

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0313

EpiControl

AF:

0.0322

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 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

0.060

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.2

DANN

Benign

0.69

DEOGEN2

Benign

0.055

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.72

.;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.95

L;L;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.2

N;N;D

REVEL

Benign

0.29

Sift

Benign

0.18

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.042

MPC

0.088

ClinPred

0.0010

GERP RS

-4.4

Varity_R

0.032

gMVP

0.23

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