19-35718078-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014727.3(KMT2B):c.60C>T(p.Phe20=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000699 in 987,210 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (2 hom.)
• Consequence: KMT2B NM_014727.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.874

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-35718078-C-T is Benign according to our data. Variant chr19-35718078-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 708351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.874 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000955 (14/146618) while in subpopulation EAS AF= 0.00176 (9/5110). AF 95% confidence interval is 0.000918. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.60C>T	p.Phe20=	synonymous_variant	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.60C>T	p.Phe20=	synonymous_variant	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.60C>T	p.Phe20=	synonymous_variant	1/37			A2
KMT2B	ENST00000692961.1	c.60C>T	p.Phe20=	synonymous_variant, NMD_transcript_variant	1/36
KMT2B	ENST00000687718.1	c.60C>T	p.Phe20=	synonymous_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.0000956 AC: 14 AN: 146510 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.000988

GnomAD4 exome AF: 0.0000654 AC: 55 AN: 840592 Hom.: 2 Cov.: 30 AF XY: 0.0000283 AC XY: 11 AN XY: 389044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.0000955 AC: 14 AN: 146618 Hom.: 0 Cov.: 32 AF XY: 0.0000981 AC XY: 7 AN XY: 71390

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00176

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.000978

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000136

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	KMT2B: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	13
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1390031315; hg19: chr19-36208980;