chr12-49024652-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003482.4(KMT2D):c.15978T>G(p.Leu5326Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,796 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 78 hom., cov: 32)

Exomes 𝑓: 0.029 ( 722 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.10

Publications

10 publications found

Variant links:

COSMIC-nc: COSV56410067

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, ClinGen
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=-0.57).

BP6

Variant 12-49024652-A-C is Benign according to our data. Variant chr12-49024652-A-C is described in ClinVar as Benign. ClinVar VariationId is 94189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.1 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3822/152224) while in subpopulation NFE AF = 0.036 (2451/68016). AF 95% confidence interval is 0.0348. There are 78 homozygotes in GnomAd4. There are 1874 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3822 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.15978T>G	p.Leu5326Leu	synonymous	Exon 51 of 55	NP_003473.3	O14686-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.15978T>G	p.Leu5326Leu	synonymous	Exon 51 of 55	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2		c.15978T>G	p.Leu5326Leu	synonymous	Exon 51 of 56	ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1		c.15987T>G	p.Leu5329Leu	synonymous	Exon 50 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3824

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0228

Gnomad FIN

AF:

0.0545

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0360

Gnomad OTH

AF:

0.0234

GnomAD2 exomes

AF:

0.0269

AC:

6691

AN:

249048

AF XY:

0.0273

show subpopulations

Gnomad AFR exome

AF:

0.00407

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.0212

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0482

Gnomad NFE exome

AF:

0.0336

Gnomad OTH exome

AF:

0.0304

GnomAD4 exome

AF:

0.0290

AC:

42322

AN:

1461572

Hom.:

722

Cov.:

AF XY:

0.0289

AC XY:

21009

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00400

AC:

134

AN:

33478

American (AMR)

AF:

0.0175

AC:

780

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0223

AC:

582

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.0262

AC:

2262

AN:

86236

European-Finnish (FIN)

AF:

0.0466

AC:

2489

AN:

53392

Middle Eastern (MID)

AF:

0.0271

AC:

156

AN:

5766

European-Non Finnish (NFE)

AF:

0.0308

AC:

34254

AN:

1111804

Other (OTH)

AF:

0.0275

AC:

1659

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2256

4511

6767

9022

11278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1196

2392

3588

4784

5980

<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:

0.0251

AC:

3822

AN:

152224

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1874

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00470

AC:

195

AN:

41530

American (AMR)

AF:

0.0213

AC:

326

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0228

AC:

110

AN:

4822

European-Finnish (FIN)

AF:

0.0545

AC:

578

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0360

AC:

2451

AN:

68016

Other (OTH)

AF:

0.0232

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

187

374

560

747

934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0316

Hom.:

Bravo

AF:

0.0205

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0332

EpiControl

AF:

0.0334

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

6.2

(source)

DANN

Benign

0.73

PhyloP100

-1.1

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over