7-152205112-C-G

Position:

• chr7-152205112-C-G

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.3955G>C​(p.Asp1319His) variant causes a missense change. The variant allele was found at a frequency of 0.0066 in 1,610,346 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 30)
  • Exomes 𝑓: 0.0067 (61 hom.)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 6.73

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 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=0.009700209).
• BP6: Variant 7-152205112-C-G is Benign according to our data. Variant chr7-152205112-C-G is described in ClinVar as [Benign]. Clinvar id is 134747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 809 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3	c.3955G>C	p.Asp1319His	missense_variant	25/59	ENST00000262189.11	NP_733751.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11	c.3955G>C	p.Asp1319His	missense_variant	25/59	1	NM_170606.3	ENSP00000262189	P2

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 808 AN: 151888 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00644

Gnomad FIN AF: 0.00694

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00787

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00607 AC: 1500 AN: 247098 Hom.: 15 AF XY: 0.00673 AC XY: 899 AN XY: 133644

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00277

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00727

Gnomad NFE exome AF: 0.00787

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00674 AC: 9822 AN: 1458340 Hom.: 61 Cov.: 29 AF XY: 0.00690 AC XY: 5007 AN XY: 725570

Gnomad4 AFR exome AF: 0.000930

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.00680

Gnomad4 NFE exome AF: 0.00717

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00532 AC: 809 AN: 152006 Hom.: 7 Cov.: 30 AF XY: 0.00538 AC XY: 400 AN XY: 74306

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00577

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00665

Gnomad4 FIN AF: 0.00694

Gnomad4 NFE AF: 0.00787

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00707 Hom.: 2

Bravo AF: 0.00453

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00622 AC: 755

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KMT2C: PP2, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 06, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	.;D
MetaRNN	Benign	0.0097	T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.45
MVP		0.82
MPC		2.5
ClinPred		0.012	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.52

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: rs138119145; hg19: chr7-151902197; COSMIC: COSV51434487;