chr12-49050762-G-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.2826C>T(p.Ile942Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,609,518 control chromosomes in the GnomAD database, including 121,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 11787 hom., cov: 31)

Exomes 𝑓: 0.39 ( 110011 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.145

Publications

34 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=-0.64).

BP6

Variant 12-49050762-G-A is Benign according to our data. Variant chr12-49050762-G-A is described in ClinVar as Benign. ClinVar VariationId is 94206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.145 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.2826C>T	p.Ile942Ile	synonymous_variant	Exon 12 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.2826C>T	p.Ile942Ile	synonymous_variant	Exon 12 of 55	5	NM_003482.4	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2 link	c.2826C>T	p.Ile942Ile	synonymous_variant	Exon 12 of 56			ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1 link	c.2826C>T	p.Ile942Ile	synonymous_variant	Exon 11 of 54			ENSP00000509386.1	O14686-3
KMT2D	ENST00000692637.1 link	c.2826C>T	p.Ile942Ile	synonymous_variant	Exon 11 of 54			ENSP00000509666.1	A0A8I5KSG1

Frequencies

GnomAD3 genomes

AF:

0.391

AC:

59288

AN:

151652

Hom.:

11760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.424

Gnomad AMI

AF:

0.354

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.248

Gnomad EAS

AF:

0.410

Gnomad SAS

AF:

0.463

Gnomad FIN

AF:

0.412

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.359

GnomAD2 exomes

AF:

0.375

AC:

92076

AN:

245850

AF XY:

0.380

show subpopulations

Gnomad AFR exome

AF:

0.425

Gnomad AMR exome

AF:

0.266

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.422

Gnomad FIN exome

AF:

0.413

Gnomad NFE exome

AF:

0.377

Gnomad OTH exome

AF:

0.362

GnomAD4 exome

AF:

0.386

AC:

562046

AN:

1457748

Hom.:

110011

Cov.:

AF XY:

0.387

AC XY:

280178

AN XY:

724438

show subpopulations

African (AFR)

AF:

0.429

AC:

14340

AN:

33396

American (AMR)

AF:

0.272

AC:

12127

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

6707

AN:

26054

East Asian (EAS)

AF:

0.377

AC:

14928

AN:

39546

South Asian (SAS)

AF:

0.443

AC:

38184

AN:

86120

European-Finnish (FIN)

AF:

0.412

AC:

21942

AN:

53218

Middle Eastern (MID)

AF:

0.275

AC:

1581

AN:

5754

European-Non Finnish (NFE)

AF:

0.387

AC:

429188

AN:

1108940

Other (OTH)

AF:

0.383

AC:

23049

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

18467

36934

55401

73868

92335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13458

26916

40374

53832

67290

<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:

0.391

AC:

59366

AN:

151770

Hom.:

11787

Cov.:

AF XY:

0.391

AC XY:

28986

AN XY:

74148

show subpopulations

African (AFR)

AF:

0.425

AC:

17570

AN:

41354

American (AMR)

AF:

0.327

AC:

4987

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.248

AC:

858

AN:

3466

East Asian (EAS)

AF:

0.410

AC:

2107

AN:

5138

South Asian (SAS)

AF:

0.464

AC:

2234

AN:

4816

European-Finnish (FIN)

AF:

0.412

AC:

4352

AN:

10558

Middle Eastern (MID)

AF:

0.267

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.385

AC:

26102

AN:

67862

Other (OTH)

AF:

0.358

AC:

756

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1765

3531

5296

7062

8827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.371

Hom.:

15272

Bravo

AF:

0.380

Asia WGS

AF:

0.433

AC:

1504

AN:

3478

EpiCase

AF:

0.374

EpiControl

AF:

0.368

ClinVar

Significance: Benign

Submissions summary: Benign:9

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 -

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

- -

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 57% of patients studied by a panel of primary immunodeficiencies. Number of patients: 54. Only high quality variants are reported. -

Jul 02, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

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

- -

Kabuki syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome 1

Benign:1

Aug 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

-0.64

CADD

Benign

1.5

(source)

DANN

Benign

0.57

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over