chr7-152162598-G-A

Position:

• chr7-152162598-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_170606.3(KMT2C):​c.10979C>T​(p.Ser3660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0444 in 1,614,162 control chromosomes in the GnomAD database, including 2,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3660S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (158 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2038 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.97

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 in gene, where missense usually causes diseases (based on misZ statistic), KMT2C. . Gene score misZ 2.1357 (greater than the threshold 3.09). Trascript score misZ 4.2875 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Kleefstra syndrome 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015626252).
• BP6: Variant 7-152162598-G-A is Benign according to our data. Variant chr7-152162598-G-A is described in ClinVar as [Benign]. Clinvar id is 134792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.10979C>T	p.Ser3660Leu	missense_variant	43/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.10979C>T	p.Ser3660Leu	missense_variant	43/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5462 AN: 152174 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.00866

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.0770

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0429

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0477 AC: 11984 AN: 251438 Hom.: 463 AF XY: 0.0497 AC XY: 6761 AN XY: 135902

Gnomad AFR exome AF: 0.00689

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.173

Gnomad SAS exome AF: 0.0706

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0400

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0453 AC: 66282 AN: 1461870 Hom.: 2038 Cov.: 33 AF XY: 0.0463 AC XY: 33697 AN XY: 727238

Gnomad4 AFR exome AF: 0.00556

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.172

Gnomad4 SAS exome AF: 0.0697

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0424

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0359 AC: 5462 AN: 152292 Hom.: 158 Cov.: 32 AF XY: 0.0370 AC XY: 2757 AN XY: 74464

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.0766

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0430

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0442 Hom.: 359

Bravo AF: 0.0352

TwinsUK AF: 0.0418 AC: 155

ALSPAC AF: 0.0467 AC: 180

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0383 AC: 329

ExAC AF: 0.0477 AC: 5788

Asia WGS AF: 0.0960 AC: 333 AN: 3478

EpiCase AF: 0.0413

EpiControl AF: 0.0374

ClinVar

Significance: Benign

Submissions summary: Benign:2 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 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2020	This variant is associated with the following publications: (PMID: 24965397) -

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	0.063
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	3.8
DANN	Benign	0.35
DEOGEN2	Benign	0.12	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.68	.;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.78	.;.;T
Polyphen		0.0020	B;B;.
Vest4		0.067
MPC		0.070
ClinPred		0.014	T
GERP RS		1.7
Varity_R		0.060
gMVP		0.14

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: rs74483926; hg19: chr7-151859683; COSMIC: COSV51370572; COSMIC: COSV51370572;