7-152249894-C-G

Variant names:

• chr7-152249894-C-G
• rs141579002
• NM_170606.3:c.1795G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_170606.3(KMT2C):​c.1795G>C​(p.Asp599His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D599Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.172
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Kleefstra syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, Broad Center for Mendelian Genomics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05102718).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.1795G>C	p.Asp599His	missense	Exon 13 of 59	NP_733751.2	Q8NEZ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.1795G>C	p.Asp599His	missense	Exon 13 of 59	ENSP00000262189.6	Q8NEZ4-1
	KMT2C	ENST00000682283.1		c.1795G>C	p.Asp599His	missense	Exon 13 of 60	ENSP00000507485.1	Q8NEZ4-3
	KMT2C	ENST00000679882.1		c.1795G>C	p.Asp599His	missense	Exon 13 of 56	ENSP00000506154.1	A0A7P0TAI3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.28
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.17
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.27
Sift	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.094
MutPred		0.11		Gain of catalytic residue at L601 (P = 0.0577)
MVP		0.11
MPC		0.041
ClinPred		0.98	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.27
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141579002; hg19: chr7-151946979;