rs201681639

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_003482.4(KMT2D):c.8578C>T(p.Arg2860Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,598,412 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2860H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.33

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2D. . Gene score misZ 3.7288 (greater than the threshold 3.09). Trascript score misZ 4.6964 (greater than threshold 3.09). GenCC has associacion of gene with Kabuki syndrome, branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, Kabuki syndrome 1, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.

BP6

Variant 12-49038778-G-A is Benign according to our data. Variant chr12-49038778-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445613.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.8578C>T	p.Arg2860Cys	missense_variant	35/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.8578C>T	p.Arg2860Cys	missense_variant	35/55	5	NM_003482.4	A2	O14686-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000690

AC:

AN:

217372

Hom.:

AF XY:

0.0000846

AC XY:

AN XY:

118218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000146

Gnomad OTH exome

AF:

0.000185

GnomAD4 exome

AF:

0.000207

AC:

300

AN:

1446240

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

135

AN XY:

718144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000234

Gnomad4 OTH exome

AF:

0.000619

GnomAD4 genome

AF:

0.000118

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000147

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 11, 2017

- -

KMT2D-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2023

The KMT2D c.8578C>T variant is predicted to result in the amino acid substitution p.Arg2860Cys. This variant was reported in an individual with Kabuki syndrome (Faundes et al 2019. PubMed ID: 30459467) and in an individual with bilateral small kidneys (Patient B2451 in Supplementary Table S1, Connaughton DM et al 2019. PubMed ID: 30773290). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-49432561-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Kabuki syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.74

MetaRNN

Uncertain

0.68

MetaSVM

Uncertain

0.088

MutationAssessor

Benign

0.55

MutationTaster

Benign

0.92

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

Polyphen

1.0

Vest4

0.56

MVP

0.53

MPC

0.75

ClinPred

0.37

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.19

gMVP

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over