dbSNP rs1555184624: KMT2D:p.Lys5490ArgfsTer21 (chr12-49022093-CTT-C) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_003482.4(KMT2D):c.16469_16470delAA(p.Lys5490ArgfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2D
NM_003482.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.44

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, 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

KMT2D links:

ENSG00000288710 (HGNC:):

ENSG00000288710 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-49022093-CTT-C is Pathogenic according to our data. Variant chr12-49022093-CTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1172600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.16469_16470delAA	p.Lys5490ArgfsTer21	frameshift	Exon 54 of 55	NP_003473.3	O14686-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.16469_16470delAA	p.Lys5490ArgfsTer21	frameshift	Exon 54 of 55	ENSP00000301067.7	O14686-1
ENSG00000288710	ENST00000683988.1		n.440_441delAA		non_coding_transcript_exon	Exon 4 of 16	ENSP00000506939.1	A0A804HI77
KMT2D	ENST00000683543.2		c.16517_16518delAA	p.Lys5506ArgfsTer21	frameshift	Exon 55 of 56	ENSP00000506726.1	A0A804HHR9

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Kabuki syndrome 1 (1)

Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=2/198

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over