12-49051406-TGGCTCCTCAGGCCGGGGGGACAGGTGC-TGGCTCCTCAGGCCGGGGGGACAGGTGCGGCTCCTCAGGCCGGGGGGACAGGTGC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_003482.4(KMT2D):​c.2250_2276dupGCACCTGTCCCCCCGGCCTGAGGAGCC​(p.Pro759_His760insHisLeuSerProArgProGluGluPro) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,603,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0500
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4
Nonframeshift variant in NON repetitive region in NM_003482.4.
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2DNM_003482.4 linkuse as main transcriptc.2250_2276dupGCACCTGTCCCCCCGGCCTGAGGAGCC p.Pro759_His760insHisLeuSerProArgProGluGluPro disruptive_inframe_insertion 11/55 ENST00000301067.12 NP_003473.3 O14686-1Q59FG6Q6PIA1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkuse as main transcriptc.2250_2276dupGCACCTGTCCCCCCGGCCTGAGGAGCC p.Pro759_His760insHisLeuSerProArgProGluGluPro disruptive_inframe_insertion 11/555 NM_003482.4 ENSP00000301067.7 O14686-1
KMT2DENST00000683543.2 linkuse as main transcriptc.2250_2276dupGCACCTGTCCCCCCGGCCTGAGGAGCC p.Pro759_His760insHisLeuSerProArgProGluGluPro disruptive_inframe_insertion 11/56 ENSP00000506726.1 A0A804HHR9
KMT2DENST00000685166.1 linkuse as main transcriptc.2250_2276dupGCACCTGTCCCCCCGGCCTGAGGAGCC p.Pro759_His760insHisLeuSerProArgProGluGluPro disruptive_inframe_insertion 10/54 ENSP00000509386.1 O14686-3
KMT2DENST00000692637.1 linkuse as main transcriptc.2250_2276dupGCACCTGTCCCCCCGGCCTGAGGAGCC p.Pro759_His760insHisLeuSerProArgProGluGluPro disruptive_inframe_insertion 10/54 ENSP00000509666.1 A0A8I5KSG1

Frequencies

GnomAD3 genomes
AF:
0.0000209
AC:
3
AN:
143218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000264
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000307
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000206
AC:
5
AN:
242168
Hom.:
0
AF XY:
0.0000302
AC XY:
4
AN XY:
132466
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:
0.0000984
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000185
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000959
AC:
14
AN:
1459790
Hom.:
0
Cov.:
37
AF XY:
0.00000964
AC XY:
7
AN XY:
726166
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000990
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000209
AC:
3
AN:
143218
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
70096
show subpopulations
Gnomad4 AFR
AF:
0.0000264
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000307
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 07, 2021In-frame insertion of 9 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs587778449; hg19: chr12-49445189; API