rs74483926

chr7-152162598-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_170606.3(KMT2C):c.10979C>T(p.Ser3660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,614,162 control chromosomes in the GnomAD database, including 2,196 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S3660S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (158 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2038 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.97

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2C
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015626252).
• BP6: Variant 7-152162598-G-A is Benign according to our data. Variant chr7-152162598-G-A is described in ClinVar as [Benign]. Clinvar id is 134792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.10979C>T	p.Ser3660Leu	missense_variant	43/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.10979C>T	p.Ser3660Leu	missense_variant	43/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5462 AN: 152174 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.00866

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0429

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0477 AC: 11984 AN: 251438 Hom.: 463 AF XY: 0.0497 AC XY: 6761 AN XY: 135902

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.173

Gnomad SAS exome AF: 0.0706

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0400

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0453 AC: 66282 AN: 1461870 Hom.: 2038 Cov.: 33 AF XY: 0.0463 AC XY: 33697 AN XY: 727238

Gnomad4 AFR exome AF: 0.00556

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0697

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0424

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0359 AC: 5462 AN: 152292 Hom.: 158 Cov.: 32 AF XY: 0.0370 AC XY: 2757 AN XY: 74464

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.0766

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0430

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0442 Hom.: 359

Bravo AF: 0.0352

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0383 AC: 329

ExAC AF: 0.0477 AC: 5788

Asia WGS AF: 0.0960 AC: 333 AN: 3478

EpiCase AF: 0.0413

EpiControl AF: 0.0374

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2020	This variant is associated with the following publications: (PMID: 24965397) -
Benign, criteria provided, single submitter	clinical testing	Invitae	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	0.063
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	3.8
Dann	Benign	0.35
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.34	N
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.36	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.067
MPC		0.070
ClinPred		0.014	T
GERP RS		1.7
Varity_R		0.060
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

Other links and lift over

dbSNP: rs74483926; hg19: chr7-151859683; COSMIC: COSV51370572; COSMIC: COSV51370572;