chr12-49051400-TAGGTGTGGCTCCTCAGGCCGGGGGGAC-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_003482.4(KMT2D):c.2256_2282delGTCCCCCCGGCCTGAGGAGCCACACCT(p.Ser753_Leu761del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,442,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.36

Publications

0 publications found

Variant links:

COSMIC-nc: COSV56428395

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: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_003482.4.

BP6

Variant 12-49051400-TAGGTGTGGCTCCTCAGGCCGGGGGGAC-T is Benign according to our data. Variant chr12-49051400-TAGGTGTGGCTCCTCAGGCCGGGGGGAC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158753.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.2256_2282delGTCCCCCCGGCCTGAGGAGCCACACCT	p.Ser753_Leu761del	disruptive_inframe_deletion	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KMT2D	ENST00000301067.12 link	c.2256_2282delGTCCCCCCGGCCTGAGGAGCCACACCT	p.Ser753_Leu761del	disruptive_inframe_deletion	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2 link	c.2256_2282delGTCCCCCCGGCCTGAGGAGCCACACCT	p.Ser753_Leu761del	disruptive_inframe_deletion	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1 link	c.2256_2282delGTCCCCCCGGCCTGAGGAGCCACACCT	p.Ser753_Leu761del	disruptive_inframe_deletion	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1 link	c.2256_2282delGTCCCCCCGGCCTGAGGAGCCACACCT	p.Ser753_Leu761del	disruptive_inframe_deletion	Exon 10 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes

AF:

0.000161

AC:

AN:

92980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000963

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000172

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000273

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000544

AC:

AN:

239170

AF XY:

0.0000534

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.0000280

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000986

AC:

133

AN:

1349482

Hom.:

AF XY:

0.000112

AC XY:

AN XY:

672366

show subpopulations

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

African (AFR)

AF:

0.0000347

AC:

AN:

28820

American (AMR)

AF:

0.0000797

AC:

AN:

37660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21440

East Asian (EAS)

AF:

0.00

AC:

AN:

30662

South Asian (SAS)

AF:

0.0000725

AC:

AN:

82708

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

47280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5136

European-Non Finnish (NFE)

AF:

0.000106

AC:

111

AN:

1043212

Other (OTH)

AF:

0.0000761

AC:

AN:

52564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.387

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000161

AC:

AN:

92980

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

46342

show subpopulations

African (AFR)

AF:

0.0000424

AC:

AN:

23562

American (AMR)

AF:

0.0000963

AC:

AN:

10380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2342

East Asian (EAS)

AF:

0.00

AC:

AN:

2550

South Asian (SAS)

AF:

0.00

AC:

AN:

2542

European-Finnish (FIN)

AF:

0.000172

AC:

AN:

5816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000273

AC:

AN:

43938

Other (OTH)

AF:

0.00

AC:

AN:

1382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000122

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BS2 -

Aug 24, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome

Benign:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

1.4

Mutation Taster

=139/61

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