chr19-35718020-T-TGGC

Variant names:

• chr19-35718020-T-TGGC
• rs898578503
• NM_014727.3:c.14_16dupCGG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BS1 BS2

The NM_014727.3(KMT2B):​c.14_16dupCGG​(p.Ala5dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 983,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KMT2B NM_014727.3 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.788
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_014727.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-35718020-T-TGGC is Benign according to our data. Variant chr19-35718020-T-TGGC is described in ClinVar as Likely_benign. ClinVar VariationId is 1556241.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000215 (18/837310) while in subpopulation AFR AF = 0.000379 (6/15846). AF 95% confidence interval is 0.000164. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 Unknown,AD gene.

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.14_16dupCGG	p.Ala5dup	disruptive_inframe_insertion	Exon 1 of 37	NP_055542.1	Q9UMN6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.14_16dupCGG	p.Ala5dup	disruptive_inframe_insertion	Exon 1 of 37	ENSP00000398837.2	Q9UMN6
	KMT2B	ENST00000673918.2		c.14_16dupCGG	p.Ala5dup	disruptive_inframe_insertion	Exon 1 of 37	ENSP00000501283.1	A0A669KBI7
	KMT2B	ENST00000687718.1		n.14_16dupCGG		non_coding_transcript_exon	Exon 1 of 3	ENSP00000510535.1	A0A8I5KWP7

Frequencies

GnomAD3 genomes AF: 0.0000888 AC: 13 AN: 146452 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000215 AC: 18 AN: 837310 Hom.: 0 Cov.: 30 AF XY: 0.0000129 AC XY: 5 AN XY: 387148

African (AFR) AF: 0.000379 AC: 6 AN: 15846

American (AMR) AF: 0.00 AC: 0 AN: 1122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5240

East Asian (EAS) AF: 0.000264 AC: 1 AN: 3782

South Asian (SAS) AF: 0.00 AC: 0 AN: 17120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1640

European-Non Finnish (NFE) AF: 0.0000144 AC: 11 AN: 764302

Other (OTH) AF: 0.00 AC: 0 AN: 27566

GnomAD4 genome AF: 0.0000887 AC: 13 AN: 146558 Hom.: 0 Cov.: 32 AF XY: 0.000126 AC XY: 9 AN XY: 71304

African (AFR) AF: 0.000196 AC: 8 AN: 40840

American (AMR) AF: 0.000202 AC: 3 AN: 14850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5008

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65820

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.79
Mutation Taster		=17/183	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs898578503; hg19: chr19-36208922;