dbSNP rs898578503: KMT2B:p.Ala4_Ala5del (chr19-35718020-TGGCGGC-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4

The NM_014727.3(KMT2B):c.11_16delCGGCGG(p.Ala4_Ala5del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A4A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2B
NM_014727.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.737

Publications

0 publications found

Variant links:

Genes affected

KMT2B (HGNC:15840): (lysine methyltransferase 2B) This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines, and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene, however, the full length nature of the shorter transcript is not known. [provided by RefSeq, Jul 2008]

KMT2B Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder with motor features
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dystonia 28, childhood-onset
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
intellectual developmental disorder, autosomal dominant 68
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

KMT2B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_014727.3.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014727.3. 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
	KMT2B	NM_014727.3	MANE Select	c.11_16delCGGCGG	p.Ala4_Ala5del	disruptive_inframe_deletion	Exon 1 of 37	NP_055542.1	Q9UMN6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.11_16delCGGCGG	p.Ala4_Ala5del	disruptive_inframe_deletion	Exon 1 of 37	ENSP00000398837.2	Q9UMN6
KMT2B	ENST00000673918.2		c.11_16delCGGCGG	p.Ala4_Ala5del	disruptive_inframe_deletion	Exon 1 of 37	ENSP00000501283.1	A0A669KBI7
KMT2B	ENST00000687718.1		n.11_16delCGGCGG		non_coding_transcript_exon	Exon 1 of 3	ENSP00000510535.1	A0A8I5KWP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

837312

Hom.:

AF XY:

0.00

AC XY:

AN XY:

387150

African (AFR)

AF:

0.00

AC:

AN:

15846

American (AMR)

AF:

0.00

AC:

AN:

1122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5240

East Asian (EAS)

AF:

0.00

AC:

AN:

3782

South Asian (SAS)

AF:

0.00

AC:

AN:

17120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

692

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

764304

Other (OTH)

AF:

0.00

AC:

AN:

27566

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over