rs34546217

Variant names:

• chr12-49022263-TC-T
• rs34546217
• NM_003482.4:c.16412+16delG

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+16delG 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]

ENSG00000288710 (HGNC:):

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 rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.16412+16delG		intron_variant	Intron 53 of 54	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.16412+16delG		intron_variant	Intron 53 of 54	5	NM_003482.4	ENSP00000301067.7
ENSG00000288710	ENST00000683988.1	n.383+16delG		intron_variant	Intron 3 of 15			ENSP00000506939.1

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

Apr 06, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Kabuki syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome 1 Benign:1

Aug 23, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;