rs34546217

chr12-49022263-TC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003482.4(KMT2D):c.16412+16del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,602,132 control chromosomes in the GnomAD database, including 96,375 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6630 hom., cov: 23)
  • Exomes 𝑓: 0.35 (89745 hom.)
• Consequence: KMT2D NM_003482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.832

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-49022263-TC-T is Benign according to our data. Variant chr12-49022263-TC-T is described in ClinVar as [Benign]. Clinvar id is 94193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49022263-TC-T is described in Lovd as [Likely_benign]. Variant chr12-49022263-TC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.16412+16del		intron_variant		ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.16412+16del		intron_variant		5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40444 AN: 151964 Hom.: 6631 Cov.: 23

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.320 AC: 79303 AN: 247488 Hom.: 13735 AF XY: 0.331 AC XY: 44441 AN XY: 134242

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.435

Gnomad SAS exome AF: 0.400

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.346 AC: 501016 AN: 1450050 Hom.: 89745 Cov.: 0 AF XY: 0.347 AC XY: 249913 AN XY: 719228

Gnomad4 AFR exome AF: 0.0577

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.397

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.266 AC: 40448 AN: 152082 Hom.: 6630 Cov.: 23 AF XY: 0.269 AC XY: 19997 AN XY: 74324

Gnomad4 AFR AF: 0.0755

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.423

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.349

Gnomad4 OTH AF: 0.261

Alfa AF: 0.293 Hom.: 1291

Bravo AF: 0.246

Asia WGS AF: 0.387 AC: 1344 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 53% of patients studied by a panel of primary immunodeficiencies. Number of patients: 50. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Kabuki syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 23, 2018

- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs34546217; hg19: chr12-49416046;