7-152183068-C-T

Variant names:

• chr7-152183068-C-T
• rs138819584
• NM_170606.3:c.5171G>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.5171G>A​(p.Ser1724Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1724I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• 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=0.09581864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2C	NM_170606.3	c.5171G>A	p.Ser1724Asn	missense_variant	Exon 35 of 59	ENST00000262189.11	NP_733751.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11	c.5171G>A	p.Ser1724Asn	missense_variant	Exon 35 of 59	1	NM_170606.3	ENSP00000262189.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 2 Uncertain:1

Apr 06, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.80
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	-0.014
Eigen_PC	Benign	0.033
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.014	D;D
Polyphen		0.13	B;B
Vest4		0.21
MutPred		0.14		Loss of phosphorylation at S1724 (P = 0.006);Loss of phosphorylation at S1724 (P = 0.006);
MVP		0.38
MPC		0.074
ClinPred		0.72	D
GERP RS		3.8
PromoterAI		0.0098	Neutral
Varity_R		0.19
gMVP		0.069
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs138819584; hg19: chr7-151880153;