rs563948892

chr7-152181999-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.5861C>G(p.Ser1954Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,614,060 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (1 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 7.99

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=0.04971102).
• BP6: Variant 7-152181999-G-C is Benign according to our data. Variant chr7-152181999-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 134760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.5861C>G	p.Ser1954Cys	missense_variant	36/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.5861C>G	p.Ser1954Cys	missense_variant	36/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251200 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00141

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461886 Hom.: 1 Cov.: 33 AF XY: 0.0000578 AC XY: 42 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000963

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000529

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	KMT2C: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Mar 04, 2023	- -

KMT2C-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

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	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Benign	0.80
DEOGEN2	Benign	0.17	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D
Polyphen		0.97	D;D
Vest4		0.39
MutPred		0.21		Gain of catalytic residue at S1956 (P = 0.0581);Gain of catalytic residue at S1956 (P = 0.0581);
MVP		0.26
MPC		0.29
ClinPred		0.097	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.42

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: rs563948892; hg19: chr7-151879084; COSMIC: COSV51441452; COSMIC: COSV51441452;