12-49026426-C-T

Variant names:

• chr12-49026426-C-T
• rs149393179
• NM_003482.4:c.15540G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_003482.4(KMT2D):​c.15540G>A​(p.Val5180Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V5180V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.42
• 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: G2P, Illumina
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-49026426-C-T is Benign according to our data. Variant chr12-49026426-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2635222.
• BP7: Synonymous conserved (PhyloP=-2.41 with no splicing effect.

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.15540G>A	p.Val5180Val	synonymous	Exon 49 of 55	NP_003473.3	O14686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.15540G>A	p.Val5180Val	synonymous	Exon 49 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.15540G>A	p.Val5180Val	synonymous	Exon 49 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.15549G>A	p.Val5183Val	synonymous	Exon 48 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Kabuki syndrome (1)
-	1	-	KMT2D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.3
DANN	Benign	0.72
PhyloP100		-2.4
PromoterAI		-0.0026	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

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

Other links and lift over

dbSNP: rs149393179; hg19: chr12-49420209;