chr12-49032195-T-C

Position:

• chr12-49032195-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003482.4(KMT2D):​c.12510A>G​(p.Pro4170Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,612,274 control chromosomes in the GnomAD database, including 97,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6672 hom., cov: 33)
  • Exomes 𝑓: 0.35 (90801 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.643

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=-0.6).
• BP6: Variant 12-49032195-T-C is Benign according to our data. Variant chr12-49032195-T-C is described in ClinVar as [Benign]. Clinvar id is 94158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49032195-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.643 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.12510A>G	p.Pro4170Pro	synonymous_variant	40/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.12510A>G	p.Pro4170Pro	synonymous_variant	40/55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40557 AN: 152072 Hom.: 6673 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.321 AC: 79586 AN: 247818 Hom.: 13888 AF XY: 0.332 AC XY: 44669 AN XY: 134580

Gnomad AFR exome AF: 0.0641

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.437

Gnomad SAS exome AF: 0.400

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.347 AC: 506210 AN: 1460084 Hom.: 90801 Cov.: 66 AF XY: 0.349 AC XY: 253160 AN XY: 726044

Gnomad4 AFR exome AF: 0.0579

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.398

Gnomad4 SAS exome AF: 0.396

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.267 AC: 40560 AN: 152190 Hom.: 6672 Cov.: 33 AF XY: 0.270 AC XY: 20067 AN XY: 74398

Gnomad4 AFR AF: 0.0754

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.424

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.262

Alfa AF: 0.318 Hom.: 3576

Bravo AF: 0.246

Asia WGS AF: 0.387 AC: 1345 AN: 3478

EpiCase AF: 0.340

EpiControl AF: 0.334

ClinVar

Significance: Benign

Submissions summary: Benign:10

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)	Oct 05, 2016	- -
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	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.8
DANN	Benign	0.63

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: rs3741622; hg19: chr12-49425978; COSMIC: COSV56407671; COSMIC: COSV56407671;