KMT2B p.Glu2354Lys

Variant names:

• chr19-35733773-G-A
• rs190929421
• NM_014727.3:c.7060G>A
• KMT2B p.Glu2354Lys

Your query was ambiguous. Multiple possible variants found:

• chr19-35733773-G-A
• chr19-35733773-GAA-AAG

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014727.3(KMT2B):​c.7060G>A​(p.Glu2354Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.15
• Publications: 1 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, Genomics England PanelApp, Orphanet
• intellectual developmental disorder, autosomal dominant 68

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027403355).
• BP6: Variant 19-35733773-G-A is Benign according to our data. Variant chr19-35733773-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430821.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00021 (32/152156) while in subpopulation AMR AF = 0.00111 (17/15288). AF 95% confidence interval is 0.000708. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 32 AD,Unknown 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.7060G>A	p.Glu2354Lys	missense	Exon 30 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.7060G>A	p.Glu2354Lys	missense	Exon 30 of 37	ENSP00000398837.2	Q9UMN6
	KMT2B	ENST00000673918.2		c.6994G>A	p.Glu2332Lys	missense	Exon 30 of 37	ENSP00000501283.1	A0A669KBI7
	KMT2B	ENST00000691421.1		c.2191G>A	p.Glu731Lys	missense	Exon 8 of 8	ENSP00000508674.1	A0A8I5KUL1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152038 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000169 AC: 42 AN: 248636 AF XY: 0.000141

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461234 Hom.: 0 Cov.: 35 AF XY: 0.000144 AC XY: 105 AN XY: 726920

African (AFR) AF: 0.0000598 AC: 2 AN: 33454

American (AMR) AF: 0.000604 AC: 27 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000131 AC: 146 AN: 1111578

Other (OTH) AF: 0.000298 AC: 18 AN: 60342

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74382

African (AFR) AF: 0.0000963 AC: 4 AN: 41518

American (AMR) AF: 0.00111 AC: 17 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67974

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.21
Sift	Uncertain	0.013	D
Sift4G	Benign	0.16	T
PromoterAI		0.013	Neutral
Varity_R		0.15
gMVP		0.53
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs190929421;

hg19: chr19-36224674;