rs55776244

Positions:

• chr12-49048778-CAG-C

Variant summary

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

The NM_003482.4(KMT2D):​c.4021-11_4021-10del variant causes a splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0335 in 1,562,362 control chromosomes in the GnomAD database, including 1,417 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (451 hom., cov: 32)
  • Exomes 𝑓: 0.031 (966 hom.)
• Consequence: KMT2D NM_003482.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.66

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 12-49048778-CAG-C is Benign according to our data. Variant chr12-49048778-CAG-C is described in ClinVar as [Benign]. Clinvar id is 94214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49048778-CAG-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.4021-11_4021-10del		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	c.4021-11_4021-10del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_003482.4	ENSP00000301067	A2

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 9249 AN: 152168 Hom.: 447 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0542

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0530

GnomAD3 exomes AF: 0.0352 AC: 8583 AN: 243616 Hom.: 228 AF XY: 0.0334 AC XY: 4417 AN XY: 132398

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0251

Gnomad FIN exome AF: 0.0476

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0306 AC: 43129 AN: 1410076 Hom.: 966 AF XY: 0.0301 AC XY: 21100 AN XY: 701784

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0254

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.0460

Gnomad4 NFE exome AF: 0.0284

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0609 AC: 9277 AN: 152286 Hom.: 451 Cov.: 32 AF XY: 0.0595 AC XY: 4429 AN XY: 74460

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0381

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.0542

Gnomad4 NFE AF: 0.0349

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0497 Hom.: 55

Bravo AF: 0.0616

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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)		0.010		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: rs55776244; hg19: chr12-49442561;