rs75226229

Variant names:

• chr12-49051245-G-A
• rs75226229
• NM_003482.4:c.2438C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49051245-G-A
• chr12-49051245-G-C
• chr12-49051245-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003482.4(KMT2D):​c.2438C>T​(p.Pro813Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,534,894 control chromosomes in the GnomAD database, including 2,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P813R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.042 (202 hom., cov: 28)
  • Exomes 𝑓: 0.051 (2163 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.479
• Publications: 27 publications found

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]

KMT2D Gene-Disease associations (from GenCC):

• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015470386).
• BP6: Variant 12-49051245-G-A is Benign according to our data. Variant chr12-49051245-G-A is described in ClinVar as Benign. ClinVar VariationId is 94202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.2438C>T	p.Pro813Leu	missense	Exon 11 of 55	NP_003473.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.2438C>T	p.Pro813Leu	missense	Exon 11 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.2438C>T	p.Pro813Leu	missense	Exon 11 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.2438C>T	p.Pro813Leu	missense	Exon 10 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6300 AN: 151202 Hom.: 202 Cov.: 28

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.0665

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.0240

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0372

GnomAD2 exomes AF: 0.0420 AC: 7835 AN: 186726 AF XY: 0.0426

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0196

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.000125

Gnomad FIN exome AF: 0.0952

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0511 AC: 70729 AN: 1383574 Hom.: 2163 Cov.: 34 AF XY: 0.0503 AC XY: 34266 AN XY: 681452

African (AFR) AF: 0.00688 AC: 213 AN: 30956

American (AMR) AF: 0.0205 AC: 693 AN: 33806

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 489 AN: 21164

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39132

South Asian (SAS) AF: 0.0136 AC: 1002 AN: 73796

European-Finnish (FIN) AF: 0.0942 AC: 4733 AN: 50252

Middle Eastern (MID) AF: 0.00741 AC: 40 AN: 5400

European-Non Finnish (NFE) AF: 0.0569 AC: 61041 AN: 1072106

Other (OTH) AF: 0.0441 AC: 2512 AN: 56962

GnomAD4 genome AF: 0.0416 AC: 6299 AN: 151320 Hom.: 202 Cov.: 28 AF XY: 0.0426 AC XY: 3149 AN XY: 73916

African (AFR) AF: 0.0107 AC: 439 AN: 41208

American (AMR) AF: 0.0345 AC: 525 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 83 AN: 3456

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5158

South Asian (SAS) AF: 0.0100 AC: 48 AN: 4800

European-Finnish (FIN) AF: 0.0981 AC: 1029 AN: 10486

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0596 AC: 4032 AN: 67690

Other (OTH) AF: 0.0368 AC: 77 AN: 2094

Alfa AF: 0.0493 Hom.: 108

Bravo AF: 0.0344

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0592 AC: 228

ESP6500AA AF: 0.0112 AC: 45

ESP6500EA AF: 0.0515 AC: 424

ExAC AF: 0.0389 AC: 4672

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	1	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.94
DANN	Benign	0.37
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.48
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.023
Sift	Benign	0.055	T
Polyphen		0.0	B
Vest4		0.048
MPC		0.19
ClinPred		0.00026	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.12
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75226229; hg19: chr12-49445028; COSMIC: COSV56410262; COSMIC: COSV56410262;