rs190995850

chr12-49042122-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):c.6076A>G(p.Ile2026Val) variant causes a missense change. The variant allele was found at a frequency of 0.000677 in 1,613,738 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (6 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.99

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.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.00936085).
• BP6: Variant 12-49042122-T-C is Benign according to our data. Variant chr12-49042122-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 500446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00365 (556/152264) while in subpopulation AFR AF= 0.013 (542/41550). AF 95% confidence interval is 0.0121. There are 2 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 556 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.6076A>G	p.Ile2026Val	missense_variant	29/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.6076A>G	p.Ile2026Val	missense_variant	29/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000884 AC: 220 AN: 248874 Hom.: 0 AF XY: 0.000570 AC XY: 77 AN XY: 135026

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000367 AC: 536 AN: 1461474 Hom.: 6 Cov.: 33 AF XY: 0.000318 AC XY: 231 AN XY: 727018

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.00365 AC: 556 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74452

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000524 Hom.: 1

Bravo AF: 0.00403

ESP6500AA AF: 0.0148 AC: 62

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	This variant is associated with the following publications: (PMID: 30459467) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 28, 2017

- -

Kabuki syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	-0.14	N
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Polyphen		0.0090	B
Vest4		0.45
MVP		0.30
MPC		0.71
ClinPred		0.011	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.47

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: rs190995850; hg19: chr12-49435905; COSMIC: COSV56436285; COSMIC: COSV56436285;