12-49051631-A-T

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.2052T>A(p.Pro684Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000607 in 1,572,820 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00061 ( 4 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.289

Publications

0 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=-0.85).

BP6

Variant 12-49051631-A-T is Benign according to our data. Variant chr12-49051631-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.289 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000589 (88/149528) while in subpopulation SAS AF = 0.00403 (19/4714). AF 95% confidence interval is 0.00264. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.2052T>A	p.Pro684Pro	synonymous_variant	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.2052T>A	p.Pro684Pro	synonymous_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2 link	c.2052T>A	p.Pro684Pro	synonymous_variant	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1 link	c.2052T>A	p.Pro684Pro	synonymous_variant	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1 link	c.2052T>A	p.Pro684Pro	synonymous_variant	Exon 10 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes

AF:

0.000589

AC:

AN:

149422

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000498

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000199

Gnomad ASJ

AF:

0.00896

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00403

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0132

Gnomad NFE

AF:

0.000370

Gnomad OTH

AF:

0.00195

GnomAD2 exomes

AF:

0.000828

AC:

182

AN:

219750

AF XY:

0.000860

show subpopulations

Gnomad AFR exome

AF:

0.0000662

Gnomad AMR exome

AF:

0.0000932

Gnomad ASJ exome

AF:

0.00867

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000104

Gnomad NFE exome

AF:

0.000492

Gnomad OTH exome

AF:

0.000948

GnomAD4 exome

AF:

0.000608

AC:

866

AN:

1423292

Hom.:

Cov.:

AF XY:

0.000693

AC XY:

487

AN XY:

702774

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32886

American (AMR)

AF:

0.000165

AC:

AN:

42416

Ashkenazi Jewish (ASJ)

AF:

0.00854

AC:

199

AN:

23306

East Asian (EAS)

AF:

0.00

AC:

AN:

39330

South Asian (SAS)

AF:

0.00331

AC:

264

AN:

79710

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51712

Middle Eastern (MID)

AF:

0.00376

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.000284

AC:

309

AN:

1089734

Other (OTH)

AF:

0.00109

AC:

AN:

58616

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

107

160

214

267

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:

0.000589

AC:

AN:

149528

Hom.:

Cov.:

AF XY:

0.000603

AC XY:

AN XY:

73028

show subpopulations

African (AFR)

AF:

0.0000496

AC:

AN:

40284

American (AMR)

AF:

0.000199

AC:

AN:

15080

Ashkenazi Jewish (ASJ)

AF:

0.00896

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

4986

South Asian (SAS)

AF:

0.00403

AC:

AN:

4714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10260

Middle Eastern (MID)

AF:

0.0143

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000370

AC:

AN:

67486

Other (OTH)

AF:

0.00193

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00165

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2D: BP4, BP7, BS1

not specified

Benign:2

Apr 10, 2018

Genetic Services Laboratory, University of Chicago

Significance: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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.85

CADD

Benign

8.3

(source)

DANN

Benign

0.59

PhyloP100

0.29

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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