rs3741626

chr12-49040626-G-Achr12-49040626-G-Cchr12-49040626-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003482.4(KMT2D):c.7144C>T(p.Pro2382Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,613,568 control chromosomes in the GnomAD database, including 240 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. P2382P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (215 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 6.61

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=0.0025892258).
• BP6: Variant 12-49040626-G-A is Benign according to our data. Variant chr12-49040626-G-A is described in ClinVar as [Benign]. Clinvar id is 94247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49040626-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.7144C>T	p.Pro2382Ser	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.7144C>T	p.Pro2382Ser	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00800 AC: 1217 AN: 152030 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0855

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00640

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.0122 AC: 3034 AN: 248290 Hom.: 69 AF XY: 0.0121 AC XY: 1635 AN XY: 134988

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.0810

Gnomad SAS exome AF: 0.0176

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00947 AC: 13834 AN: 1461420 Hom.: 215 Cov.: 35 AF XY: 0.00952 AC XY: 6923 AN XY: 727008

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.0791

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.0122

Gnomad4 NFE exome AF: 0.00689

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.00798 AC: 1214 AN: 152148 Hom.: 25 Cov.: 32 AF XY: 0.00900 AC XY: 669 AN XY: 74372

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0847

Gnomad4 SAS AF: 0.0247

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.00640

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00575 Hom.: 1

Bravo AF: 0.00636

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000737 AC: 3

ESP6500EA AF: 0.00514 AC: 43

ExAC AF: 0.0119 AC: 1445

Asia WGS AF: 0.0440 AC: 152 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00468

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5 Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Kabuki syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	22
Dann	Benign	0.91
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Polyphen		0.83	P
Vest4		0.54
MPC		0.65
ClinPred		0.050	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.15

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: rs3741626; hg19: chr12-49434409; COSMIC: COSV56429597; COSMIC: COSV56429597;