chr12-49040100-G-A

Variant names:

• chr12-49040100-G-A
• rs189888707
• NM_003482.4:c.7670C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):​c.7670C>T​(p.Pro2557Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00761 in 1,613,868 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2557P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (91 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 3.75
• Publications: 18 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=0.005523622).
• BP6: Variant 12-49040100-G-A is Benign according to our data. Variant chr12-49040100-G-A is described in ClinVar as Benign. ClinVar VariationId is 94250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0103 (1569/152320) while in subpopulation SAS AF = 0.017 (82/4834). AF 95% confidence interval is 0.0155. There are 14 homozygotes in GnomAd4. There are 786 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1569 AD gene.

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.7670C>T	p.Pro2557Leu	missense	Exon 32 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.7670C>T	p.Pro2557Leu	missense	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.7670C>T	p.Pro2557Leu	missense	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.7679C>T	p.Pro2560Leu	missense	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1575 AN: 152202 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00824 AC: 2043 AN: 248030 AF XY: 0.00890

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00733 AC: 10709 AN: 1461548 Hom.: 91 Cov.: 32 AF XY: 0.00775 AC XY: 5632 AN XY: 727044

African (AFR) AF: 0.0158 AC: 529 AN: 33476

American (AMR) AF: 0.00769 AC: 344 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 406 AN: 26130

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.0178 AC: 1538 AN: 86240

European-Finnish (FIN) AF: 0.00127 AC: 68 AN: 53352

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.00619 AC: 6882 AN: 1111814

Other (OTH) AF: 0.0117 AC: 708 AN: 60362

GnomAD4 genome AF: 0.0103 AC: 1569 AN: 152320 Hom.: 14 Cov.: 33 AF XY: 0.0106 AC XY: 786 AN XY: 74478

African (AFR) AF: 0.0165 AC: 685 AN: 41574

American (AMR) AF: 0.0169 AC: 258 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4834

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00615 AC: 418 AN: 68022

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.00773 Hom.: 15

Bravo AF: 0.0105

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0140 AC: 54

ESP6500EA AF: 0.00702 AC: 58

ExAC AF: 0.00834 AC: 1008

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00979

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6 Other:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 21, 2014

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Jun 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:4

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 14, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Kabuki syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Polyphen		0.0020	B
Vest4		0.38
MVP		0.18
MPC		0.65
ClinPred		0.021	T
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.12
gMVP		0.13
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs189888707; hg19: chr12-49433883; COSMIC: COSV56411192; COSMIC: COSV56411192;