rs61730545

chr7-152176208-G-Achr7-152176208-G-Cchr7-152176208-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_170606.3(KMT2C):c.9245C>T(p.Pro3082Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,605,798 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3082T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (68 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 8.07

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=0.0094693005).
• BP6: Variant 7-152176208-G-A is Benign according to our data. Variant chr7-152176208-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152176208-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00118 (180/152282) while in subpopulation SAS AF= 0.0222 (107/4826). AF 95% confidence interval is 0.0188. There are 3 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.9245C>T	p.Pro3082Leu	missense_variant	38/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.9245C>T	p.Pro3082Leu	missense_variant	38/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152164 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00378 AC: 928 AN: 245804 Hom.: 25 AF XY: 0.00470 AC XY: 625 AN XY: 132900

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000149

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0272

Gnomad FIN exome AF: 0.00164

Gnomad NFE exome AF: 0.000681

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00205 AC: 2986 AN: 1453516 Hom.: 68 Cov.: 33 AF XY: 0.00276 AC XY: 1996 AN XY: 722418

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.000138

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0264

Gnomad4 FIN exome AF: 0.00164

Gnomad4 NFE exome AF: 0.000444

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152282 Hom.: 3 Cov.: 31 AF XY: 0.00146 AC XY: 109 AN XY: 74452

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000691 Hom.: 1

Bravo AF: 0.000533

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00440 AC: 534

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 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	Jan 01, 2024	KMT2C: PM5, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 20, 2023	- -

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	Uncertain	0.45
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0095	T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.80
MVP		0.64
MPC		0.45
ClinPred		0.085	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61730545; hg19: chr7-151873293; COSMIC: COSV51485941; COSMIC: COSV51485941;