rs77652527

chr7-152252650-T-C

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.1365A>G(p.Ile455Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,613,196 control chromosomes in the GnomAD database, including 1,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I455V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.025 (77 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1167 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.0770

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=0.0062871873).
• BP6: Variant 7-152252650-T-C is Benign according to our data. Variant chr7-152252650-T-C is described in ClinVar as [Benign]. Clinvar id is 134736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152252650-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.025 (3815/152324) while in subpopulation NFE AF= 0.0401 (2726/68018). AF 95% confidence interval is 0.0388. There are 77 homozygotes in gnomad4. There are 1743 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3817 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.1365A>G	p.Ile455Met	missense_variant	10/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.1365A>G	p.Ile455Met	missense_variant	10/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3817 AN: 152206 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.00704

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0238 AC: 5971 AN: 250670 Hom.: 109 AF XY: 0.0241 AC XY: 3265 AN XY: 135480

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00611

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0374

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0368 AC: 53792 AN: 1460872 Hom.: 1167 Cov.: 30 AF XY: 0.0358 AC XY: 26049 AN XY: 726778

Gnomad4 AFR exome AF: 0.00598

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00589

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0438

Gnomad4 OTH exome AF: 0.0298

GnomAD4 genome AF: 0.0250 AC: 3815 AN: 152324 Hom.: 77 Cov.: 32 AF XY: 0.0234 AC XY: 1743 AN XY: 74492

Gnomad4 AFR AF: 0.00702

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0268

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0363 Hom.: 170

Bravo AF: 0.0241

TwinsUK AF: 0.0467 AC: 173

ALSPAC AF: 0.0488 AC: 188

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0434 AC: 373

ExAC AF: 0.0230 AC: 2790

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0361

EpiControl AF: 0.0382

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	14
Dann	Benign	0.77
DEOGEN2	Benign	0.095	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.53	D
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.20
Sift	Benign	0.15	T;T
Polyphen		0.0040	B;B
Vest4		0.17
MPC		0.039
ClinPred		0.0034	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77652527; hg19: chr7-151949735; COSMIC: COSV104384013; COSMIC: COSV104384013;