NM_003482.4:c.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC(p.His751_Pro759del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,603,084 control chromosomes in the GnomAD database, including 11 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P750P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 8 hom., cov: 31)

Exomes 𝑓: 0.00058 ( 3 hom. )

Consequence

KMT2D
NM_003482.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 1.58

Publications

1 publications found

Variant links:

COSMIC-nc: COSV56411648

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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_003482.4.

BP6

Variant 12-49051406-TGGCTCCTCAGGCCGGGGGGACAGGTGC-T is Benign according to our data. Variant chr12-49051406-TGGCTCCTCAGGCCGGGGGGACAGGTGC-T is described in ClinVar as [Likely_benign]. Clinvar id is 134661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00537 (769/143318) while in subpopulation AFR AF = 0.019 (722/38012). AF 95% confidence interval is 0.0178. There are 8 homozygotes in GnomAd4. There are 362 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 769 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC	p.His751_Pro759del	disruptive_inframe_deletion	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.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC	p.His751_Pro759del	disruptive_inframe_deletion	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2 link	c.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC	p.His751_Pro759del	disruptive_inframe_deletion	Exon 11 of 56			ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1 link	c.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC	p.His751_Pro759del	disruptive_inframe_deletion	Exon 10 of 54			ENSP00000509386.1	O14686-3
KMT2D	ENST00000692637.1 link	c.2250_2276delGCACCTGTCCCCCCGGCCTGAGGAGCC	p.His751_Pro759del	disruptive_inframe_deletion	Exon 10 of 54			ENSP00000509666.1	A0A8I5KSG1

Frequencies

GnomAD3 genomes

AF:

0.00535

AC:

766

AN:

143200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00156

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000677

Gnomad FIN

AF:

0.000203

Gnomad MID

AF:

0.00794

Gnomad NFE

AF:

0.0000920

Gnomad OTH

AF:

0.00601

GnomAD2 exomes

AF:

0.00128

AC:

309

AN:

242168

AF XY:

0.00101

show subpopulations

Gnomad AFR exome

AF:

0.0187

Gnomad AMR exome

AF:

0.000669

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000224

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000120

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000579

AC:

845

AN:

1459766

Hom.:

AF XY:

0.000549

AC XY:

399

AN XY:

726154

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0182

AC:

606

AN:

33258

American (AMR)

AF:

0.000964

AC:

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39644

South Asian (SAS)

AF:

0.000255

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52940

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000936

AC:

104

AN:

1111072

Other (OTH)

AF:

0.00109

AC:

AN:

60276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00537

AC:

769

AN:

143318

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

362

AN XY:

70210

show subpopulations

African (AFR)

AF:

0.0190

AC:

722

AN:

38012

American (AMR)

AF:

0.00156

AC:

AN:

14718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.00

AC:

AN:

4676

South Asian (SAS)

AF:

0.000452

AC:

AN:

4426

European-Finnish (FIN)

AF:

0.000203

AC:

AN:

9856

Middle Eastern (MID)

AF:

0.00833

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000920

AC:

AN:

65192

Other (OTH)

AF:

0.00594

AC:

AN:

2020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00388

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

Apr 13, 2016

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

- -

May 30, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=158/42

polymorphism

(source)

Splicing

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