rs55776396

chr12-49024652-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003482.4(KMT2D):c.15978T>G(p.Leu5326=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,796 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (78 hom., cov: 32)
  • Exomes 𝑓: 0.029 (722 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.10

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-49024652-A-C is Benign according to our data. Variant chr12-49024652-A-C is described in ClinVar as [Benign]. Clinvar id is 94189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49024652-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3822/152224) while in subpopulation NFE AF= 0.036 (2451/68016). AF 95% confidence interval is 0.0348. There are 78 homozygotes in gnomad4. There are 1874 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3824 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.15978T>G	p.Leu5326=	synonymous_variant	51/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.15978T>G	p.Leu5326=	synonymous_variant	51/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3824 AN: 152106 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0269 AC: 6691 AN: 249048 Hom.: 116 AF XY: 0.0273 AC XY: 3694 AN XY: 135114

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.0212

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0261

Gnomad FIN exome AF: 0.0482

Gnomad NFE exome AF: 0.0336

Gnomad OTH exome AF: 0.0304

GnomAD4 exome AF: 0.0290 AC: 42322 AN: 1461572 Hom.: 722 Cov.: 31 AF XY: 0.0289 AC XY: 21009 AN XY: 727064

Gnomad4 AFR exome AF: 0.00400

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0223

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0262

Gnomad4 FIN exome AF: 0.0466

Gnomad4 NFE exome AF: 0.0308

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0251 AC: 3822 AN: 152224 Hom.: 78 Cov.: 32 AF XY: 0.0252 AC XY: 1874 AN XY: 74442

Gnomad4 AFR AF: 0.00470

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.0360

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0316 Hom.: 53

Bravo AF: 0.0205

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0332

EpiControl AF: 0.0334

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2012	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	6.2
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs55776396; hg19: chr12-49418435; COSMIC: COSV56410067; COSMIC: COSV56410067;