chr19-35718061-T-C

Variant names:

• chr19-35718061-T-C
• rs1306123854
• NM_014727.3:c.43T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014727.3(KMT2B):​c.43T>C​(p.Ser15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 145,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.747
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• intellectual developmental disorder, autosomal dominant 68

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16526684).

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.43T>C	p.Ser15Pro	missense	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.43T>C	p.Ser15Pro	missense	Exon 1 of 37	ENSP00000398837.2	Q9UMN6
	KMT2B	ENST00000673918.2		c.43T>C	p.Ser15Pro	missense	Exon 1 of 37	ENSP00000501283.1	A0A669KBI7
	KMT2B	ENST00000687718.1		n.43T>C		non_coding_transcript_exon	Exon 1 of 3	ENSP00000510535.1	A0A8I5KWP7

Frequencies

GnomAD3 genomes AF: 0.00000686 AC: 1 AN: 145798 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000686 AC: 1 AN: 145798 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 70902

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000246 AC: 1 AN: 40594

American (AMR) AF: 0.00 AC: 0 AN: 14738

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65640

Other (OTH) AF: 0.00 AC: 0 AN: 2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Benign	0.57
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.75
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		0.0080	B
Vest4		0.30
MutPred		0.14		Loss of phosphorylation at S15 (P = 0.0063)
MVP		0.43
ClinPred		0.32	T
GERP RS		2.0
PromoterAI		-0.059	Neutral
Varity_R		0.22
gMVP		0.11
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs1306123854; hg19: chr19-36208963;