rs189888707

chr12-49040100-G-Achr12-49040100-G-Cchr12-49040100-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):c.7670C>T(p.Pro2557Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00761 in 1,613,868 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2557P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (91 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 3.75

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.005523622).
• BP6: Variant 12-49040100-G-A is Benign according to our data. Variant chr12-49040100-G-A is described in ClinVar as [Benign]. Clinvar id is 94250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49040100-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0103 (1569/152320) while in subpopulation SAS AF= 0.017 (82/4834). AF 95% confidence interval is 0.0155. There are 14 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1575 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.7670C>T	p.Pro2557Leu	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.7670C>T	p.Pro2557Leu	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1575 AN: 152202 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00824 AC: 2043 AN: 248030 Hom.: 24 AF XY: 0.00890 AC XY: 1200 AN XY: 134780

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00733 AC: 10709 AN: 1461548 Hom.: 91 Cov.: 32 AF XY: 0.00775 AC XY: 5632 AN XY: 727044

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.00769

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.00619

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152320 Hom.: 14 Cov.: 33 AF XY: 0.0106 AC XY: 786 AN XY: 74478

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00615

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00804 Hom.: 8

Bravo AF: 0.0105

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0140 AC: 54

ESP6500EA AF: 0.00702 AC: 58

ExAC AF: 0.00834 AC: 1008

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00979

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Kabuki syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Benign	0.88
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Polyphen		0.0020	B
Vest4		0.38
MVP		0.18
MPC		0.65
ClinPred		0.021	T
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.12
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs189888707; hg19: chr12-49433883; COSMIC: COSV56411192; COSMIC: COSV56411192;