12-49040661-C-G

Position:

chr12-49040661-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_003482.4(KMT2D):c.7109G>C(p.Arg2370Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,412 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.696

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 -5 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=0.28226712).

BP6

Variant 12-49040661-C-G is Benign according to our data. Variant chr12-49040661-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283811.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.7109G>C	p.Arg2370Pro	missense_variant	32/55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.7109G>C	p.Arg2370Pro	missense_variant	32/55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151812

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000523

AC:

AN:

248504

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151812

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74136

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 10, 2017

- -

Kabuki syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.054

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.94

REVEL

Uncertain

0.44

Sift

Uncertain

0.0030

Polyphen

0.016

Vest4

0.66

MutPred

0.24

Gain of glycosylation at T2375 (P = 0.0735);

MVP

0.55

MPC

0.76

ClinPred

0.13

GERP RS

5.3

Varity_R

0.27

gMVP

0.22

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