chr12-49054680-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.248G>A(p.Arg83Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 1,612,688 control chromosomes in the GnomAD database, including 733 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 73 hom., cov: 32)

Exomes 𝑓: 0.027 ( 660 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.648

Publications

21 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=0.00251621).

BP6

Variant 12-49054680-C-T is Benign according to our data. Variant chr12-49054680-C-T is described in ClinVar as Benign. ClinVar VariationId is 94203.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 = 0.0242 (3680/152244) while in subpopulation NFE AF = 0.0344 (2338/68006). AF 95% confidence interval is 0.0332. There are 73 homozygotes in GnomAd4. There are 1820 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3680 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.248G>A	p.Arg83Gln	missense	Exon 4 of 55	NP_003473.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.248G>A	p.Arg83Gln	missense	Exon 4 of 55	ENSP00000301067.7
KMT2D	ENST00000683543.2		c.248G>A	p.Arg83Gln	missense	Exon 4 of 56	ENSP00000506726.1
KMT2D	ENST00000685166.1		c.248G>A	p.Arg83Gln	missense	Exon 3 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3682

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00447

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0209

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.0542

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0259

AC:

6318

AN:

243934

AF XY:

0.0264

show subpopulations

Gnomad AFR exome

AF:

0.00421

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0211

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0479

Gnomad NFE exome

AF:

0.0324

Gnomad OTH exome

AF:

0.0292

GnomAD4 exome

AF:

0.0275

AC:

40154

AN:

1460444

Hom.:

660

Cov.:

AF XY:

0.0275

AC XY:

19942

AN XY:

726442

show subpopulations

African (AFR)

AF:

0.00389

AC:

130

AN:

33452

American (AMR)

AF:

0.0169

AC:

752

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.0221

AC:

576

AN:

26104

East Asian (EAS)

AF:

0.000177

AC:

AN:

39632

South Asian (SAS)

AF:

0.0250

AC:

2155

AN:

86128

European-Finnish (FIN)

AF:

0.0465

AC:

2479

AN:

53304

Middle Eastern (MID)

AF:

0.0239

AC:

138

AN:

5768

European-Non Finnish (NFE)

AF:

0.0291

AC:

32362

AN:

1111258

Other (OTH)

AF:

0.0258

AC:

1555

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2402

4804

7207

9609

12011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1134

2268

3402

4536

5670

<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:

0.0242

AC:

3680

AN:

152244

Hom.:

Cov.:

AF XY:

0.0244

AC XY:

1820

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00445

AC:

185

AN:

41546

American (AMR)

AF:

0.0209

AC:

320

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0215

AC:

104

AN:

4828

European-Finnish (FIN)

AF:

0.0542

AC:

574

AN:

10600

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0344

AC:

2338

AN:

68006

Other (OTH)

AF:

0.0223

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

186

372

557

743

929

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0294

Hom.:

249

Bravo

AF:

0.0196

TwinsUK

AF:

0.0259

AC:

ALSPAC

AF:

0.0288

AC:

111

ESP6500AA

AF:

0.00554

AC:

ESP6500EA

AF:

0.0309

AC:

256

ExAC

AF:

0.0258

AC:

3119

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

Nov 20, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jul 06, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Dec 31, 2014

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:4

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BP4, BS1, BS2

Nov 03, 2023

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

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.039

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.20

PhyloP100

0.65

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.70

REVEL

Benign

0.26

Sift

Benign

0.38

Polyphen

0.0040

Vest4

0.074

MPC

0.21

ClinPred

0.0043

GERP RS

3.3

Varity_R

0.039

gMVP

0.39

Mutation Taster

=94/6

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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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