19-35720684-C-T

Variant names:

• chr19-35720684-C-T
• rs769921695
• NM_014727.3:c.1337C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_014727.3(KMT2B):​c.1337C>T​(p.Pro446Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,481,148 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P446P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.130
• Publications: 3 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, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual developmental disorder, autosomal dominant 68

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2602406).
• BP6: Variant 19-35720684-C-T is Benign according to our data. Variant chr19-35720684-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548572.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000012 (16/1331192) while in subpopulation MID AF = 0.000574 (3/5222). AF 95% confidence interval is 0.000156. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 42. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 16 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.1337C>T	p.Pro446Leu	missense	Exon 3 of 37	NP_055542.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2B	ENST00000420124.4	TSL:1 MANE Select	c.1337C>T	p.Pro446Leu	missense	Exon 3 of 37	ENSP00000398837.2
	KMT2B	ENST00000673918.2		c.1271C>T	p.Pro424Leu	missense	Exon 3 of 37	ENSP00000501283.1
	KMT2B	ENST00000689139.1		c.833C>T	p.Pro278Leu	missense	Exon 1 of 4	ENSP00000509761.1

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149956 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000247

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

GnomAD2 exomes AF: 0.0000352 AC: 3 AN: 85330 AF XY: 0.0000466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000237

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000321

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 16 AN: 1331192 Hom.: 0 Cov.: 42 AF XY: 0.0000154 AC XY: 10 AN XY: 650920

African (AFR) AF: 0.00 AC: 0 AN: 29054

American (AMR) AF: 0.00 AC: 0 AN: 24248

Ashkenazi Jewish (ASJ) AF: 0.0000500 AC: 1 AN: 20004

East Asian (EAS) AF: 0.0000564 AC: 2 AN: 35476

South Asian (SAS) AF: 0.00 AC: 0 AN: 65860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45804

Middle Eastern (MID) AF: 0.000574 AC: 3 AN: 5222

European-Non Finnish (NFE) AF: 0.00000857 AC: 9 AN: 1050552

Other (OTH) AF: 0.0000182 AC: 1 AN: 54972

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149956 Hom.: 0 Cov.: 24 AF XY: 0.0000137 AC XY: 1 AN XY: 73074

African (AFR) AF: 0.0000247 AC: 1 AN: 40524

American (AMR) AF: 0.00 AC: 0 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5000

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67456

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.0000875 Hom.: 0

ExAC AF: 0.0000208 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Dystonia 28, childhood-onset (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.7
DANN	Benign	0.93
DEOGEN2	Benign	0.026	T
Eigen	Benign	0.025
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.0066	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.13
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.037	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.33		Loss of glycosylation at P446 (P = 0.0025)
MVP		0.39
ClinPred		0.22	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.20
Mutation Taster		=86/14	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: rs769921695; hg19: chr19-36211586;