rs142070663

chr7-152182273-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_170606.3(KMT2C):c.5587C>G(p.Pro1863Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,614,092 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (10 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.626

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2C
• BP4: Computational evidence support a benign effect (MetaRNN=0.0058739483).
• BP6: Variant 7-152182273-G-C is Benign according to our data. Variant chr7-152182273-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 134757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 368 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.5587C>G	p.Pro1863Ala	missense_variant	36/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.5587C>G	p.Pro1863Ala	missense_variant	36/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 368 AN: 152174 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00208 AC: 523 AN: 250918 Hom.: 1 AF XY: 0.00194 AC XY: 263 AN XY: 135584

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00359 AC: 5241 AN: 1461800 Hom.: 10 Cov.: 33 AF XY: 0.00351 AC XY: 2552 AN XY: 727202

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00436

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.00242 AC: 368 AN: 152292 Hom.: 2 Cov.: 31 AF XY: 0.00216 AC XY: 161 AN XY: 74462

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00381

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00330 Hom.: 1

Bravo AF: 0.00264

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	KMT2C: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

KMT2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as likely 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	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	0.29
Dann	Benign	0.44
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D;D
Polyphen		0.31	B;B
Vest4		0.083
MVP		0.38
MPC		0.077
ClinPred		0.045	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.21

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

Other links and lift over

dbSNP: rs142070663; hg19: chr7-151879358; COSMIC: COSV51307061; COSMIC: COSV51307061;