rs371076182

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_003482.4(KMT2D):c.2062C>T(p.Arg688Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,578,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0430

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 Benign. Variant got -13 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.20787928).

BP6

Variant 12-49051621-G-A is Benign according to our data. Variant chr12-49051621-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.2062C>T	p.Arg688Cys	missense_variant	11/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.2062C>T	p.Arg688Cys	missense_variant	11/55	5	NM_003482.4	ENSP00000301067	A2	O14686-1
KMT2D	ENST00000683543.2 linkuse as main transcript	c.2062C>T	p.Arg688Cys	missense_variant	11/56			ENSP00000506726	P4
KMT2D	ENST00000685166.1 linkuse as main transcript	c.2062C>T	p.Arg688Cys	missense_variant	10/54			ENSP00000509386	A2	O14686-3
KMT2D	ENST00000692637.1 linkuse as main transcript	c.2062C>T	p.Arg688Cys	missense_variant	10/54			ENSP00000509666	A2

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

151800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000969

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000857

AC:

AN:

221808

Hom.:

AF XY:

0.000101

AC XY:

AN XY:

118590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000415

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000121

AC:

172

AN:

1426940

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

705076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000607

Gnomad4 AMR exome

AF:

0.0000234

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000249

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000147

Gnomad4 OTH exome

AF:

0.0000851

GnomAD4 genome

AF:

0.000158

AC:

AN:

151800

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74128

show subpopulations

Gnomad4 AFR

AF:

0.0000969

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000151

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000744

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Kabuki syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

KMT2D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.82

REVEL

Benign

0.24

Sift

Benign

0.29

Polyphen

0.95

Vest4

0.26

MVP

0.35

MPC

0.25

ClinPred

0.040

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.21

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