rs142835638

chr7-152163145-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.10432C>G(p.Gln3478Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,176 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (26 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 9.31

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=0.0060453415).
• BP6: Variant 7-152163145-G-C is Benign according to our data. Variant chr7-152163145-G-C is described in ClinVar as [Benign]. Clinvar id is 134788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152163145-G-C is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 468 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.10432C>G	p.Gln3478Glu	missense_variant	43/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.10432C>G	p.Gln3478Glu	missense_variant	43/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 468 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00395 AC: 992 AN: 251446 Hom.: 4 AF XY: 0.00422 AC XY: 574 AN XY: 135914

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00634

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00444 AC: 6494 AN: 1461880 Hom.: 26 Cov.: 33 AF XY: 0.00455 AC XY: 3307 AN XY: 727242

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00661

Gnomad4 FIN exome AF: 0.00447

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00328

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74470

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00363 Hom.: 0

Bravo AF: 0.00300

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00445

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KMT2C: BS1, BS2 -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 15, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

KMT2C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	0.97
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0060	T;T;T
MetaSVM	Uncertain	0.089	D
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	0.89	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0080	D;D;D
Polyphen		0.96	D;D;.
Vest4		0.45
MVP		0.63
MPC		0.23
ClinPred		0.033	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.37

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: rs142835638; hg19: chr7-151860230; COSMIC: COSV51503272; COSMIC: COSV51503272;