chr7-152136899-A-T

Position:

• chr7-152136899-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_170606.3(KMT2C):​c.14669T>A​(p.Phe4890Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.58

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]

KMT2C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2C	NM_170606.3	c.14669T>A	p.Phe4890Tyr	missense_variant	59/59	ENST00000262189.11	NP_733751.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11	c.14669T>A	p.Phe4890Tyr	missense_variant	59/59	1	NM_170606.3	ENSP00000262189.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2019

- -

Kleefstra syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.39	N;N;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	D;.;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.019	D;.;T
Sift4G	Uncertain	0.041	.;.;D
Polyphen		0.99	D;D;.
Vest4		0.65
MutPred		0.53		Gain of ubiquitination at K4887 (P = 0.0716);Gain of ubiquitination at K4887 (P = 0.0716);.;
MVP		0.92
MPC		2.5
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.60

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: rs2089918301; hg19: chr7-151833984;