12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant names:

• chr12-49033482-T-TTGCTGCTGCTGCTGCTGCTGC
• rs398123707
• NM_003482.4:c.11202_11222dupGCAGCAGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_003482.4(KMT2D):​c.11202_11222dupGCAGCAGCAGCAGCAGCAGCA​(p.Gln3741_Gln3742insGlnGlnGlnGlnGlnGlnGln) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2D NM_003482.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57
• 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, MODERATE Submitted by: Illumina, G2P
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003482.4

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.11202_11222dupGCAGCAGCAGCAGCAGCAGCA	p.Gln3741_Gln3742insGlnGlnGlnGlnGlnGlnGln	disruptive_inframe_insertion	Exon 40 of 55	NP_003473.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.11202_11222dupGCAGCAGCAGCAGCAGCAGCA	p.Gln3741_Gln3742insGlnGlnGlnGlnGlnGlnGln	disruptive_inframe_insertion	Exon 40 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.11202_11222dupGCAGCAGCAGCAGCAGCAGCA	p.Gln3741_Gln3742insGlnGlnGlnGlnGlnGlnGln	disruptive_inframe_insertion	Exon 40 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.11211_11231dupGCAGCAGCAGCAGCAGCAGCA	p.Gln3744_Gln3745insGlnGlnGlnGlnGlnGlnGln	disruptive_inframe_insertion	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome Uncertain:1

Jan 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.11202_11222dup, results in the insertion of 7 amino acid(s) of the KMT2D protein (p.Gln3739_Gln3745dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KMT2D-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6

Splicing

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

Other links and lift over

dbSNP: rs398123707; hg19: chr12-49427265;