rs138399600

Variant names:

• chr19-35719453-C-T
• rs138399600
• NM_014727.3:c.364-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014727.3(KMT2B):​c.364-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,565,752 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (126 hom.)
• Consequence: KMT2B NM_014727.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0540
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 19-35719453-C-T is Benign according to our data. Variant chr19-35719453-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0755 is higher than 0.05.

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.364-16C>T		intron	N/A	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.364-16C>T		intron	N/A	ENSP00000398837.2	Q9UMN6
	KMT2B	ENST00000673918.2		c.364-16C>T		intron	N/A	ENSP00000501283.1	A0A669KBI7
	KMT2B	ENST00000687718.1		n.364-331C>T		intron	N/A	ENSP00000510535.1	A0A8I5KWP7

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 733 AN: 152176 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.0124 AC: 2225 AN: 178846 AF XY: 0.00950

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.0792

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00234 AC: 3307 AN: 1413458 Hom.: 126 Cov.: 30 AF XY: 0.00203 AC XY: 1422 AN XY: 699236

African (AFR) AF: 0.000560 AC: 18 AN: 32158

American (AMR) AF: 0.0778 AC: 2944 AN: 37838

Ashkenazi Jewish (ASJ) AF: 0.000198 AC: 5 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36948

South Asian (SAS) AF: 0.00 AC: 0 AN: 80256

European-Finnish (FIN) AF: 0.00153 AC: 77 AN: 50370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000902 AC: 98 AN: 1086306

Other (OTH) AF: 0.00281 AC: 165 AN: 58626

GnomAD4 genome AF: 0.00482 AC: 734 AN: 152294 Hom.: 22 Cov.: 32 AF XY: 0.00525 AC XY: 391 AN XY: 74470

African (AFR) AF: 0.000650 AC: 27 AN: 41554

American (AMR) AF: 0.0429 AC: 657 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68018

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00305 Hom.: 3

Bravo AF: 0.00926

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		0.054
PromoterAI		0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138399600; hg19: chr19-36210355;