NM_170606.3:c.3487G>A

Variant names:

• chr7-152222013-C-T
• rs142546291
• NM_170606.3:c.3487G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_170606.3(KMT2C):​c.3487G>A​(p.Val1163Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. V1163L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67
• 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: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics, Broad Center for Mendelian Genomics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22640076).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.3487G>A	p.Val1163Ile	missense	Exon 22 of 59	NP_733751.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.3487G>A	p.Val1163Ile	missense	Exon 22 of 59	ENSP00000262189.6
	KMT2C	ENST00000473186.5	TSL:1	n.1198G>A		non_coding_transcript_exon	Exon 8 of 46
	KMT2C	ENST00000682283.1		c.3487G>A	p.Val1163Ile	missense	Exon 22 of 60	ENSP00000507485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.035	N
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.23
Sift	Benign	0.14	T
Polyphen		0.43	B
Vest4		0.29
MutPred		0.17		Gain of helix (P = 0.062)
MVP		0.75
MPC		1.1
ClinPred		0.40	T
GERP RS		5.6
Varity_R		0.094
gMVP		0.26
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142546291; hg19: chr7-151919098;