rs116686402

Positions:

• chr12-49039573-G-A
• chr12-49039573-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003482.4(KMT2D):​c.8091C>T​(p.Arg2697=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,611,484 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (82 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.150

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-49039573-G-A is Benign according to our data. Variant chr12-49039573-G-A is described in ClinVar as [Benign]. Clinvar id is 94257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.8091C>T	p.Arg2697=	synonymous_variant	33/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.8091C>T	p.Arg2697=	synonymous_variant	33/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2710 AN: 152212 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00472 AC: 1159 AN: 245544 Hom.: 29 AF XY: 0.00352 AC XY: 471 AN XY: 133798

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00220 AC: 3211 AN: 1459154 Hom.: 82 Cov.: 32 AF XY: 0.00197 AC XY: 1427 AN XY: 725904

Gnomad4 AFR exome AF: 0.0683

Gnomad4 AMR exome AF: 0.00442

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.000297

Gnomad4 OTH exome AF: 0.00555

GnomAD4 genome AF: 0.0178 AC: 2716 AN: 152330 Hom.: 71 Cov.: 33 AF XY: 0.0173 AC XY: 1290 AN XY: 74484

Gnomad4 AFR AF: 0.0603

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00473 Hom.: 6

Bravo AF: 0.0203

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000891

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kabuki syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 20, 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

Oct 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.4
DANN	Benign	0.77
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: rs116686402; hg19: chr12-49433356;