rs75226229

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003482.4(KMT2D):c.2438C>T(p.Pro813Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,534,894 control chromosomes in the GnomAD database, including 2,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P813R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.042 ( 202 hom., cov: 28)

Exomes 𝑓: 0.051 ( 2163 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.479

Publications

27 publications found

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 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015470386).

BP6

Variant 12-49051245-G-A is Benign according to our data. Variant chr12-49051245-G-A is described in ClinVar as [Benign]. Clinvar id is 94202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.2438C>T	p.Pro813Leu	missense_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KMT2D	ENST00000301067.12 link	c.2438C>T	p.Pro813Leu	missense_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2 link	c.2438C>T	p.Pro813Leu	missense_variant	Exon 11 of 56			ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1 link	c.2438C>T	p.Pro813Leu	missense_variant	Exon 10 of 54			ENSP00000509386.1	O14686-3
KMT2D	ENST00000692637.1 link	c.2438C>T	p.Pro813Leu	missense_variant	Exon 10 of 54			ENSP00000509666.1	A0A8I5KSG1

Frequencies

GnomAD3 genomes

AF:

0.0417

AC:

6300

AN:

151202

Hom.:

202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0107

Gnomad AMI

AF:

0.0665

Gnomad AMR

AF:

0.0345

Gnomad ASJ

AF:

0.0240

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0981

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0596

Gnomad OTH

AF:

0.0372

GnomAD2 exomes

AF:

0.0420

AC:

7835

AN:

186726

AF XY:

0.0426

show subpopulations

Gnomad AFR exome

AF:

0.00769

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000125

Gnomad FIN exome

AF:

0.0952

Gnomad NFE exome

AF:

0.0577

Gnomad OTH exome

AF:

0.0450

GnomAD4 exome

AF:

0.0511

AC:

70729

AN:

1383574

Hom.:

2163

Cov.:

AF XY:

0.0503

AC XY:

34266

AN XY:

681452

show subpopulations

African (AFR)

AF:

0.00688

AC:

213

AN:

30956

American (AMR)

AF:

0.0205

AC:

693

AN:

33806

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

489

AN:

21164

East Asian (EAS)

AF:

0.000153

AC:

AN:

39132

South Asian (SAS)

AF:

0.0136

AC:

1002

AN:

73796

European-Finnish (FIN)

AF:

0.0942

AC:

4733

AN:

50252

Middle Eastern (MID)

AF:

0.00741

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.0569

AC:

61041

AN:

1072106

Other (OTH)

AF:

0.0441

AC:

2512

AN:

56962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3072

6145

9217

12290

15362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0416

AC:

6299

AN:

151320

Hom.:

202

Cov.:

AF XY:

0.0426

AC XY:

3149

AN XY:

73916

show subpopulations

African (AFR)

AF:

0.0107

AC:

439

AN:

41208

American (AMR)

AF:

0.0345

AC:

525

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.0240

AC:

AN:

3456

East Asian (EAS)

AF:

0.000775

AC:

AN:

5158

South Asian (SAS)

AF:

0.0100

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0981

AC:

1029

AN:

10486

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0596

AC:

4032

AN:

67690

Other (OTH)

AF:

0.0368

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

283

567

850

1134

1417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0493

Hom.:

108

Bravo

AF:

0.0344

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0592

AC:

228

ESP6500AA

AF:

0.0112

AC:

ESP6500EA

AF:

0.0515

AC:

424

ExAC

AF:

0.0389

AC:

4672

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 02, 2016

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

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.084

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.94

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.043

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-0.48

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.40

REVEL

Benign

0.023

Sift

Benign

0.055

Polyphen

0.0

Vest4

0.048

MPC

0.19

ClinPred

0.00026

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.12

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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rs75226229

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over