NM_182931.3:c.4068G>C

Variant names:

• chr7-105110868-G-C
• NM_182931.3:c.4068G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_182931.3(KMT2E):​c.4068G>C​(p.Lys1356Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1356T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KMT2E NM_182931.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.80
• Publications: 0 publications found

Genes affected

KMT2E (HGNC:18541): (lysine methyltransferase 2E (inactive)) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a protein with an N-terminal PHD zinc finger and a central SET domain. Overexpression of the protein inhibits cell cycle progression. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

SRPK2 (HGNC:11306): (SRSF protein kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including nucleic acid metabolic process; peptidyl-serine phosphorylation; and regulation of viral genome replication. Located in chromatin; cytosol; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-105110868-G-C is Pathogenic according to our data. Variant chr7-105110868-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2672119.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182931.3. 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
	KMT2E	NM_182931.3	MANE Select	c.4068G>C	p.Lys1356Asn	missense splice_region	Exon 26 of 27	NP_891847.1	Q8IZD2-1
	KMT2E	NM_018682.4		c.4068G>C	p.Lys1356Asn	missense splice_region	Exon 25 of 26	NP_061152.3
	KMT2E	NM_001410908.1		c.3942G>C	p.Lys1314Asn	missense splice_region	Exon 24 of 25	NP_001397837.1	Q8IZD2-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2E	ENST00000311117.8	TSL:1 MANE Select	c.4068G>C	p.Lys1356Asn	missense splice_region	Exon 26 of 27	ENSP00000312379.3	Q8IZD2-1
	KMT2E	ENST00000473063.2	TSL:1	c.3942G>C	p.Lys1314Asn	missense splice_region	Exon 24 of 25	ENSP00000417156.2	Q8IZD2-7
	KMT2E	ENST00000257745.9	TSL:1	n.*2707G>C		splice_region non_coding_transcript_exon	Exon 26 of 27	ENSP00000257745.5	A0A8J9FJW2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	O'Donnell-Luria-Rodan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.088	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.32		Loss of methylation at K1356 (P = 2e-04)
MVP		0.67
MPC		0.15
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.43
gMVP		0.21
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 0

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

Other links and lift over

hg19: chr7-104751315;