rs73302197

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_003482.4(KMT2D):c.6807C>T(p.Ser2269Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,610,722 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 48 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 46 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -4.16

Publications

3 publications found

Variant links:

COSMIC-nc: COSV56422193

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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 12-49040963-G-A is Benign according to our data. Variant chr12-49040963-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158780.

BP7

Synonymous conserved (PhyloP=-4.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1952/152190) while in subpopulation AFR AF = 0.0441 (1829/41512). AF 95% confidence interval is 0.0424. There are 48 homozygotes in GnomAd4. There are 917 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1952 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.6807C>T	p.Ser2269Ser	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.6807C>T	p.Ser2269Ser	synonymous_variant	Exon 32 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1948

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0441

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00332

AC:

815

AN:

245710

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.0445

Gnomad AMR exome

AF:

0.00251

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000607

Gnomad NFE exome

AF:

0.000153

Gnomad OTH exome

AF:

0.00203

GnomAD4 exome

AF:

0.00133

AC:

1938

AN:

1458532

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

846

AN XY:

725366

show subpopulations

African (AFR)

AF:

0.0450

AC:

1500

AN:

33306

American (AMR)

AF:

0.00289

AC:

128

AN:

44240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25916

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86034

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1110156

Other (OTH)

AF:

0.00256

AC:

154

AN:

60142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

110

220

329

439

549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0128

AC:

1952

AN:

152190

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

917

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0441

AC:

1829

AN:

41512

American (AMR)

AF:

0.00556

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67988

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00651

Hom.:

Bravo

AF:

0.0143

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Kabuki syndrome 1

Uncertain:1Benign:1

Sep 20, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 02, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2024

Athena Diagnostics

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

- -

not provided

Benign:1

Nov 07, 2018

GeneDx

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

-0.50

CADD

Benign

0.017

(source)

DANN

Benign

0.73

PhyloP100

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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