chr7-152247986-G-GT

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PVS1BP6_Moderate

The NM_170606.3(KMT2C):c.2447dupA(p.Tyr816fs) variant causes a frameshift, stop gained change. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.49 ( 0 hom., cov: 0)

Exomes 𝑓: 0.49 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2C
NM_170606.3 frameshift, stop_gained

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.77

Publications

24 publications found

Variant links:

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

KMT2C Gene-Disease associations (from GenCC):

Kleefstra syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics, Broad Center for Mendelian Genomics
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

KMT2C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 7-152247986-G-GT is Benign according to our data. Variant chr7-152247986-G-GT is described in ClinVar as Benign. ClinVar VariationId is 403020.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170606.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 59	NP_733751.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 59	ENSP00000262189.6
KMT2C	ENST00000682283.1		c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 60	ENSP00000507485.1
KMT2C	ENST00000679882.1		c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 56	ENSP00000506154.1

Frequencies

GnomAD3 genomes

AF:

0.495

AC:

72119

AN:

145804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.497

Gnomad AMI

AF:

0.499

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.493

Gnomad EAS

AF:

0.500

Gnomad SAS

AF:

0.498

Gnomad FIN

AF:

0.493

Gnomad MID

AF:

0.490

Gnomad NFE

AF:

0.493

Gnomad OTH

AF:

0.492

GnomAD2 exomes

AF:

0.487

AC:

81747

AN:

167790

AF XY:

0.488

show subpopulations

Gnomad AFR exome

AF:

0.471

Gnomad AMR exome

AF:

0.489

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.490

Gnomad NFE exome

AF:

0.485

Gnomad OTH exome

AF:

0.478

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff

AF:

0.492

AC:

635498

AN:

1292742

Hom.:

Cov.:

AF XY:

0.492

AC XY:

317601

AN XY:

645684

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.496

AC:

14894

AN:

30056

American (AMR)

AF:

0.495

AC:

20393

AN:

41178

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

11352

AN:

23226

East Asian (EAS)

AF:

0.500

AC:

19512

AN:

39040

South Asian (SAS)

AF:

0.498

AC:

41128

AN:

82504

European-Finnish (FIN)

AF:

0.492

AC:

24311

AN:

49462

Middle Eastern (MID)

AF:

0.491

AC:

2580

AN:

5256

European-Non Finnish (NFE)

AF:

0.490

AC:

474876

AN:

968238

Other (OTH)

AF:

0.492

AC:

26452

AN:

53782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.324

Heterozygous variant carriers

38851

77702

116552

155403

194254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

18386

36772

55158

73544

91930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.495

AC:

72179

AN:

145924

Hom.:

Cov.:

AF XY:

0.495

AC XY:

35339

AN XY:

71454

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.497

AC:

19865

AN:

40008

American (AMR)

AF:

0.494

AC:

7276

AN:

14714

Ashkenazi Jewish (ASJ)

AF:

0.493

AC:

1637

AN:

3318

East Asian (EAS)

AF:

0.500

AC:

2534

AN:

5068

South Asian (SAS)

AF:

0.498

AC:

2337

AN:

4694

European-Finnish (FIN)

AF:

0.493

AC:

4991

AN:

10120

Middle Eastern (MID)

AF:

0.489

AC:

134

AN:

274

European-Non Finnish (NFE)

AF:

0.493

AC:

31978

AN:

64842

Other (OTH)

AF:

0.493

AC:

988

AN:

2006

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.384

Heterozygous variant carriers

3433

6867

10300

13734

17167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

872

1744

2616

3488

4360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.488

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=0/200

disease causing (fs/PTC)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over