rs587778452

Variant names:

• chr12-49051497-G-A
• rs587778452
• NM_003482.4:c.2186C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49051497-G-A
• chr12-49051497-G-C
• chr12-49051497-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003482.4(KMT2D):​c.2186C>T​(p.Pro729Leu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 1.31

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10900983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.2186C>T	p.Pro729Leu	missense_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.2186C>T	p.Pro729Leu	missense_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.2186C>T	p.Pro729Leu	missense_variant	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.2186C>T	p.Pro729Leu	missense_variant	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.2186C>T	p.Pro729Leu	missense_variant	Exon 10 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Uncertain:2

Jul 18, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 01, 2022

Daryl Scott Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Polyphen		0.079	B
Vest4		0.22
MutPred		0.34		Loss of glycosylation at P729 (P = 0.0502);
MVP		0.15
MPC		0.19
ClinPred		0.20	T
GERP RS		3.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.2
Varity_R		0.11
gMVP		0.43

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: rs587778452; hg19: chr12-49445280;