rs3735156

chr7-152251983-C-Gchr7-152251983-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_170606.3(KMT2C):c.1577G>C(p.Arg526Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 1,612,278 control chromosomes in the GnomAD database, including 9,481 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R526H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (4565 hom., cov: 32)
  • Exomes 𝑓: 0.037 (4916 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.51

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2C
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029095411).
• BP6: Variant 7-152251983-C-G is Benign according to our data. Variant chr7-152251983-C-G is described in ClinVar as [Benign]. Clinvar id is 134740.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-152251983-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.1577G>C	p.Arg526Pro	missense_variant	11/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.1577G>C	p.Arg526Pro	missense_variant	11/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22736 AN: 152042 Hom.: 4537 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.0855

Gnomad SAS AF: 0.0917

Gnomad FIN AF: 0.0247

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.104

GnomAD3 exomes AF: 0.0711 AC: 17787 AN: 250254 Hom.: 2163 AF XY: 0.0624 AC XY: 8431 AN XY: 135220

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0836

Gnomad SAS exome AF: 0.0828

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0367 AC: 53543 AN: 1460118 Hom.: 4916 Cov.: 31 AF XY: 0.0364 AC XY: 26456 AN XY: 726214

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.0902

Gnomad4 SAS exome AF: 0.0823

Gnomad4 FIN exome AF: 0.0213

Gnomad4 NFE exome AF: 0.0157

Gnomad4 OTH exome AF: 0.0549

GnomAD4 genome AF: 0.150 AC: 22815 AN: 152160 Hom.: 4565 Cov.: 32 AF XY: 0.148 AC XY: 11032 AN XY: 74388

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.0896

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.0853

Gnomad4 SAS AF: 0.0914

Gnomad4 FIN AF: 0.0247

Gnomad4 NFE AF: 0.0157

Gnomad4 OTH AF: 0.103

Alfa AF: 0.0271 Hom.: 209

Bravo AF: 0.168

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.453 AC: 1996

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0762 AC: 9251

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.016	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	2.2	N;N
REVEL	Uncertain	0.40
Sift	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.032
MPC		0.046
ClinPred		0.0046	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3735156; hg19: chr7-151949068; COSMIC: COSV51371704; COSMIC: COSV51371704;