chr12-49022591-T-TG

Variant names:

• chr12-49022591-T-TG
• rs1555184787
• NM_003482.4:c.16336dupC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_SupportingO2_Very_StrongO3_Moderate

The NM_003482.4(KMT2D):c.16336dupC (p.Gln5446ProfsTer13) variant causes a frameshift, splice region change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The gene KMT2D is a tumor suppressor gene (CancerMine: 29 TSG, 29 oncogene, 10 driver citations). The gene KMT2D is a known oncogene (CancerMine: 29 TSG, 29 oncogene, 10 driver citations). The gene KMT2D is a cancer driver gene (CancerMine: 29 TSG, 29 oncogene, 10 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.49). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.49
• Publications: 0 publications found

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

KMT2D Gene-Disease associations (from GenCC):

• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Illumina, PanelApp Australia
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, ClinGen
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288710 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP (single/no review) — Supporting (O1); O1 contributing sources (1.0 pts): ClinVar germline P/LP in TSG (★)
	O2Null variant in tumour suppressor gene		Frameshift/stop-gained, NMD predicted, LoF oncogenic mechanism — O2 very strong (+8); Use caution: splice variant may lead to in-frame exon skipping; Use caution: splice variant may lead to expression of a well-known alternative isoform; Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 29 citations, oncogene: 29 citations, driver: 10 citations).; Frameshift/stop-gained. NMD predicted: true. LoF mechanism: true. Downstream pathogenic count: 0.
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KMT2D NM_003482.4	MANE Select	c.16336dupC p.Gln5446ProfsTer13	frameshiftsplice_region	Exon 52 of 55	Prot: NP_003473.3 UniProt:

KMT2D NM_003482.4

MANE Select

HGVSc / HGVSpc.16336dupCp.Gln5446ProfsTer13

Exon rankExon 52 of 55

frameshiftsplice_region

Prot: NP_003473.3UniProt: O14686-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KMT2D ENST00000301067.12	TSL:5MANE Select	c.16336dupC p.Gln5446ProfsTer13	frameshiftsplice_region	Exon 52 of 55	Prot: ENSP00000301067.7 UniProt:
	ENSG00000288710 ENST00000683988.1		n.307dupC	splice_regionnon_coding_transcript_exon	Exon 2 of 16	Prot: ENSP00000506939.1 UniProt:
	KMT2D ENST00000683543.2		c.16384dupC p.Gln5462ProfsTer13	frameshiftsplice_region	Exon 53 of 56	Prot: ENSP00000506726.1 UniProt:

KMT2D ENST00000301067.12

TSL:5MANE Select

HGVSc / HGVSpc.16336dupCp.Gln5446ProfsTer13

Exon rankExon 52 of 55

frameshiftsplice_region

Prot: ENSP00000301067.7UniProt: O14686-1

ENSG00000288710 ENST00000683988.1

HGVSc / HGVSpn.307dupC

Exon rankExon 2 of 16

splice_regionnon_coding_transcript_exon

Prot: ENSP00000506939.1UniProt: A0A804HI77

KMT2D ENST00000683543.2

HGVSc / HGVSpc.16384dupCp.Gln5462ProfsTer13

Exon rankExon 53 of 56

frameshiftsplice_region

Prot: ENSP00000506726.1UniProt: A0A804HHR9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Pathogenic	9.5

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555184787;

hg19: chr12-49416374;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar