rs141338021

chr7-152181787-A-T

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.6073T>A(p.Ser2025Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,614,162 control chromosomes in the GnomAD database, including 1 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 0.0019 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (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: 2.36

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=0.007820815).
• BP6: Variant 7-152181787-A-T is Benign according to our data. Variant chr7-152181787-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 134766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.6073T>A	p.Ser2025Thr	missense_variant	36/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.6073T>A	p.Ser2025Thr	missense_variant	36/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152152 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000489 AC: 123 AN: 251364 Hom.: 1 AF XY: 0.000361 AC XY: 49 AN XY: 135840

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1461892 Hom.: 1 Cov.: 32 AF XY: 0.000162 AC XY: 118 AN XY: 727248

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152270 Hom.: 0 Cov.: 31 AF XY: 0.00188 AC XY: 140 AN XY: 74438

Gnomad4 AFR AF: 0.00659

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000401 Hom.: 0

Bravo AF: 0.00210

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	KMT2C: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2023	- -

KMT2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

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	0.074
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	15
Dann	Benign	0.36
DEOGEN2	Benign	0.048	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.036
Sift	Benign	0.041	D;D
Polyphen		0.0010	B;B
Vest4		0.041
MVP		0.082
MPC		0.072
ClinPred		0.020	T
GERP RS		2.5
Varity_R		0.049
gMVP		0.31

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: rs141338021; hg19: chr7-151878872;