12-49040934-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.6836G>A(p.Gly2279Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.575

Publications

4 publications found

Variant links:

COSMIC-nc: COSV99040157

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 Gene-Disease associations (from GenCC):

choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
Kabuki syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Kabuki syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1510754).

BP6

Variant 12-49040934-C-T is Benign according to our data. Variant chr12-49040934-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000217 (33/152282) while in subpopulation NFE AF = 0.000412 (28/67994). AF 95% confidence interval is 0.000293. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.6836G>A	p.Gly2279Glu	missense	Exon 32 of 55	NP_003473.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.6836G>A	p.Gly2279Glu	missense	Exon 32 of 55	ENSP00000301067.7
KMT2D	ENST00000683543.2		c.6836G>A	p.Gly2279Glu	missense	Exon 32 of 56	ENSP00000506726.1
KMT2D	ENST00000685166.1		c.6845G>A	p.Gly2282Glu	missense	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000141

AC:

AN:

248452

AF XY:

0.000126

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000293

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000469

AC:

685

AN:

1461356

Hom.:

Cov.:

AF XY:

0.000446

AC XY:

324

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33474

American (AMR)

AF:

0.0000671

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000586

AC:

651

AN:

1111646

Other (OTH)

AF:

0.000398

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000217

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41564

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

67994

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000366

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00122

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 29, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 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

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KMT2D p.G2279E variant was not identified in the literature but was identified in dbSNP (ID: rs200578414) and ClinVar (classified as benign by EGL Genetic Diagnostics; and as likely benign by Athena Diagnostics Inc and Invitae for Kabuki syndrome).Â¬â€ The variant was identified in control databases in 43 of 279806 chromosomes at a frequency of 0.0001537, and was observed at the highest frequency in the Euopean (non-Finnish) population in 40 of 127886 chromosomes (freq: 0.0003128) (Genome Aggregation Database March 6, 2019, v2.1.1). This is greater than expected for the rare, autosomal dominant Kabuki syndrome associated with KMT2D variants.Â¬â€ The p.G2279 residue is not highly conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity.Â¬â€ The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing.Â¬â€ In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

Jan 09, 2014

Eurofins Ntd Llc (ga)

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

Benign:1

Feb 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Kabuki syndrome

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D-related disorder

Benign:1

Apr 13, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.052

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.15

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

0.55

PhyloP100

0.57

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

Polyphen

0.95

Vest4

0.35

MVP

0.35

MPC

0.72

ClinPred

0.051

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.16

Mutation Taster

=68/32

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over