chr12-49041018-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003482.4(KMT2D):c.6752C>T(p.Ser2251Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00164 in 1,582,118 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S2251S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 6.28

Variant links:

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]

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008974552).

BP6

Variant 12-49041018-G-A is Benign according to our data. Variant chr12-49041018-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94242.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=1, Benign=5}. Variant chr12-49041018-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00195 (297/152260) while in subpopulation AMR AF = 0.0114 (175/15300). AF 95% confidence interval is 0.0101. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.6752C>T	p.Ser2251Leu	missense_variant	Exon 32 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.6752C>T	p.Ser2251Leu	missense_variant	Exon 32 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

297

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00242

AC:

542

AN:

224340

AF XY:

0.00206

show subpopulations

Gnomad AFR exome

AF:

0.000461

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.000750

GnomAD4 exome

AF:

0.00161

AC:

2300

AN:

1429858

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1045

AN XY:

707914

show subpopulations

Gnomad4 AFR exome

AF:

0.000524

AC:

AN:

32466

Gnomad4 AMR exome

AF:

0.0122

AC:

501

AN:

41142

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

23724

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39398

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

81654

Gnomad4 FIN exome

AF:

0.000153

AC:

AN:

52150

Gnomad4 NFE exome

AF:

0.00155

AC:

1701

AN:

1094902

Gnomad4 Remaining exome

AF:

0.00124

AC:

AN:

58832

Heterozygous variant carriers

134

268

401

535

669

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00195

AC:

297

AN:

152260

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

159

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000650

AC:

0.000649663

AN:

0.000649663

Gnomad4 AMR

AF:

0.0114

AC:

0.0114379

AN:

0.0114379

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000194

AC:

0.000193723

AN:

0.000193723

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000188

AC:

0.000188288

AN:

0.000188288

Gnomad4 NFE

AF:

0.00128

AC:

0.00127937

AN:

0.00127937

Gnomad4 OTH

AF:

0.00142

AC:

0.00142045

AN:

0.00142045

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00141

Hom.:

Bravo

AF:

0.00247

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000781

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.00180

AC:

218

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 16, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28933623) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BS1 -

not specified

Benign:2Other:1

Jan 02, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Kabuki syndrome 1

Uncertain:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

0.086

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Polyphen

1.0

Vest4

0.56

MVP

0.47

MPC

0.60

ClinPred

0.025

GERP RS

5.1

Varity_R

0.21

gMVP

0.19

Mutation Taster

=87/13

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over