chr12-49040291-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003482.4(KMT2D):c.7479G>T(p.Gly2493Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,598,928 control chromosomes in the GnomAD database, including 143,531 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. G2493G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.43 ( 14147 hom., cov: 32)

Exomes 𝑓: 0.42 ( 129384 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.0400

Publications

26 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 12-49040291-C-A is Benign according to our data. Variant chr12-49040291-C-A is described in ClinVar as [Benign]. Clinvar id is 94248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.7479G>T	p.Gly2493Gly	synonymous_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.7479G>T	p.Gly2493Gly	synonymous_variant	Exon 32 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.429

AC:

65077

AN:

151750

Hom.:

14123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.466

Gnomad FIN

AF:

0.428

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.425

Gnomad OTH

AF:

0.407

GnomAD2 exomes

AF:

0.411

AC:

96468

AN:

234900

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.299

Gnomad EAS exome

AF:

0.443

Gnomad FIN exome

AF:

0.434

Gnomad NFE exome

AF:

0.424

Gnomad OTH exome

AF:

0.412

GnomAD4 exome

AF:

0.421

AC:

608568

AN:

1447060

Hom.:

129384

Cov.:

AF XY:

0.421

AC XY:

302770

AN XY:

718434

show subpopulations

African (AFR)

AF:

0.475

AC:

15730

AN:

33150

American (AMR)

AF:

0.300

AC:

13010

AN:

43332

Ashkenazi Jewish (ASJ)

AF:

0.295

AC:

7367

AN:

24966

East Asian (EAS)

AF:

0.401

AC:

15850

AN:

39554

South Asian (SAS)

AF:

0.450

AC:

38002

AN:

84418

European-Finnish (FIN)

AF:

0.435

AC:

22753

AN:

52340

Middle Eastern (MID)

AF:

0.366

AC:

2076

AN:

5672

European-Non Finnish (NFE)

AF:

0.425

AC:

468738

AN:

1103984

Other (OTH)

AF:

0.420

AC:

25042

AN:

59644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

22112

44225

66337

88450

110562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.429

AC:

65151

AN:

151868

Hom.:

14147

Cov.:

AF XY:

0.427

AC XY:

31653

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.470

AC:

19438

AN:

41384

American (AMR)

AF:

0.366

AC:

5595

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

974

AN:

3468

East Asian (EAS)

AF:

0.432

AC:

2224

AN:

5144

South Asian (SAS)

AF:

0.467

AC:

2244

AN:

4808

European-Finnish (FIN)

AF:

0.428

AC:

4520

AN:

10568

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.425

AC:

28834

AN:

67902

Other (OTH)

AF:

0.406

AC:

856

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1851

3702

5553

7404

9255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.369

Hom.:

2857

Bravo

AF:

0.420

Asia WGS

AF:

0.450

AC:

1563

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 64% of patients studied by a panel of primary immunodeficiencies. Number of patients: 61. Only high quality variants are reported. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 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

- -

not provided

Benign:3

May 12, 2020

GeneDx

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

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome 1

Benign:2

Aug 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome

Benign:1

Feb 04, 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

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.5

(source)

DANN

Benign

0.62

PhyloP100

-0.040

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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chr12-49040291-C-A

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