12-49051609-G-T

Position:

chr12-49051609-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_003482.4(KMT2D):c.2074C>A(p.Pro692Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,585,278 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 19 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 1.46

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 -15 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=0.00604105).

BP6

Variant 12-49051609-G-T is Benign according to our data. Variant chr12-49051609-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 134664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49051609-G-T is described in Lovd as [Likely_benign]. Variant chr12-49051609-G-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 431 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.2074C>A	p.Pro692Thr	missense_variant	11/55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.2074C>A	p.Pro692Thr	missense_variant	11/55	5	NM_003482.4	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2 linkuse as main transcript	c.2074C>A	p.Pro692Thr	missense_variant	11/56			ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1 linkuse as main transcript	c.2074C>A	p.Pro692Thr	missense_variant	10/54			ENSP00000509386.1	O14686-3
KMT2D	ENST00000692637.1 linkuse as main transcript	c.2074C>A	p.Pro692Thr	missense_variant	10/54			ENSP00000509666.1	A0A8I5KSG1

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

431

AN:

151918

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000799

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00499

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00348

AC:

786

AN:

225972

Hom.:

AF XY:

0.00359

AC XY:

434

AN XY:

121016

show subpopulations

Gnomad AFR exome

AF:

0.000526

Gnomad AMR exome

AF:

0.00161

Gnomad ASJ exome

AF:

0.000536

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00602

Gnomad OTH exome

AF:

0.00328

GnomAD4 exome

AF:

0.00457

AC:

6543

AN:

1433244

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3166

AN XY:

709000

show subpopulations

Gnomad4 AFR exome

AF:

0.000604

Gnomad4 AMR exome

AF:

0.00153

Gnomad4 ASJ exome

AF:

0.000292

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00163

Gnomad4 FIN exome

AF:

0.00226

Gnomad4 NFE exome

AF:

0.00547

Gnomad4 OTH exome

AF:

0.00339

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152034

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000796

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00499

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00379

Hom.:

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000483

AC:

ESP6500EA

AF:

0.00476

AC:

ExAC

AF:

0.00389

AC:

471

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	KMT2D: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2015	- -

Kabuki syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 16, 2021

- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome;CN030661:Kabuki syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 25, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.5% (677/117374) including 3 homozygotes (https://gnomad.broadinstitute.org/variant/12-49445392-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:134664). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.043

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.70

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.81

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.92

REVEL

Benign

0.18

Sift

Uncertain

0.011

Polyphen

0.0080

Vest4

0.23

MVP

0.21

MPC

0.21

ClinPred

0.0023

GERP RS

3.5

Varity_R

0.063

gMVP

0.37

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