rs138119145

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_170606.3(KMT2C):c.3955G>C(p.Asp1319His) variant causes a missense change. The variant allele was found at a frequency of 0.0066 in 1,610,346 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 30)

Exomes 𝑓: 0.0067 ( 61 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 6.73

Publications

12 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009700209).

BP6

Variant 7-152205112-C-G is Benign according to our data. Variant chr7-152205112-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00532 (809/152006) while in subpopulation NFE AF = 0.00787 (535/67978). AF 95% confidence interval is 0.00732. There are 7 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 809 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	NM_170606.3	MANE Select	c.3955G>C	p.Asp1319His	missense	Exon 25 of 59	NP_733751.2	Q8NEZ4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.3955G>C	p.Asp1319His	missense	Exon 25 of 59	ENSP00000262189.6	Q8NEZ4-1
KMT2C	ENST00000473186.5	TSL:1	n.1666G>C		non_coding_transcript_exon	Exon 11 of 46
KMT2C	ENST00000682283.1		c.3955G>C	p.Asp1319His	missense	Exon 25 of 60	ENSP00000507485.1	Q8NEZ4-3

Frequencies

GnomAD3 genomes

AF:

0.00532

AC:

808

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00577

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00644

Gnomad FIN

AF:

0.00694

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00787

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00607

AC:

1500

AN:

247098

AF XY:

0.00673

show subpopulations

Gnomad AFR exome

AF:

0.00144

Gnomad AMR exome

AF:

0.00277

Gnomad ASJ exome

AF:

0.00150

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00727

Gnomad NFE exome

AF:

0.00787

Gnomad OTH exome

AF:

0.00465

GnomAD4 exome

AF:

0.00674

AC:

9822

AN:

1458340

Hom.:

Cov.:

AF XY:

0.00690

AC XY:

5007

AN XY:

725570

show subpopulations

African (AFR)

AF:

0.000930

AC:

AN:

33322

American (AMR)

AF:

0.00287

AC:

128

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26088

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39526

South Asian (SAS)

AF:

0.0106

AC:

913

AN:

85992

European-Finnish (FIN)

AF:

0.00680

AC:

362

AN:

53262

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00717

AC:

7958

AN:

1109696

Other (OTH)

AF:

0.00533

AC:

321

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

413

826

1240

1653

2066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<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

AF:

0.00532

AC:

809

AN:

152006

Hom.:

Cov.:

AF XY:

0.00538

AC XY:

400

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

41474

American (AMR)

AF:

0.00577

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00665

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00694

AC:

AN:

10512

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00787

AC:

535

AN:

67978

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00707

Hom.:

Bravo

AF:

0.00453

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00622

AC:

755

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0097

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.5

PhyloP100

6.7

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.50

Sift

Uncertain

0.0010

Polyphen

1.0

Vest4

0.45

MVP

0.82

MPC

2.5

ClinPred

0.012

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.52

Mutation Taster

=96/4

polymorphism

(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

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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

Computational scores

Splicing

Publications

Other links and lift over