Variant chr12-49039623-C-CA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_003482.4(KMT2D):c.8047-7_8047-6insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,599,132 control chromosomes in the GnomAD database, including 40 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 30 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 10 hom. )

Consequence

KMT2D
NM_003482.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.08

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 12-49039623-C-CA is Benign according to our data. Variant chr12-49039623-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196782.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1602/151810) while in subpopulation AFR AF= 0.0358 (1483/41408). AF 95% confidence interval is 0.0343. There are 30 homozygotes in gnomad4. There are 723 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1602 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.8047-7_8047-6insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.8047-7_8047-6insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_003482.4	ENSP00000301067	A2	O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1604

AN:

151694

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00544

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00910

GnomAD3 exomes

AF:

0.00265

AC:

594

AN:

224184

Hom.:

AF XY:

0.00192

AC XY:

235

AN XY:

122476

show subpopulations

Gnomad AFR exome

AF:

0.0351

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000609

Gnomad SAS exome

AF:

0.000143

Gnomad FIN exome

AF:

0.000246

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.00109

GnomAD4 exome

AF:

0.00110

AC:

1594

AN:

1447322

Hom.:

Cov.:

AF XY:

0.000989

AC XY:

712

AN XY:

719924

show subpopulations

Gnomad4 AFR exome

AF:

0.0356

Gnomad4 AMR exome

AF:

0.00238

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000704

Gnomad4 FIN exome

AF:

0.000126

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.00280

GnomAD4 genome

AF:

0.0106

AC:

1602

AN:

151810

Hom.:

Cov.:

AF XY:

0.00974

AC XY:

723

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.0358

Gnomad4 AMR

AF:

0.00543

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00900

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Kabuki syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 22, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2015	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over