rs774164988

Variant names:

• chr12-49041293-G-A
• rs774164988
• NM_003482.4:c.6477C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49041293-G-A
• chr12-49041293-G-C
• chr12-49041293-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003482.4(KMT2D):​c.6477C>T​(p.Leu2159Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000833 in 1,525,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2159L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-49041293-G-A is Benign according to our data. Variant chr12-49041293-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BS2: High AC in GnomAd4 at 12 AD gene.

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.6477C>T	p.Leu2159Leu	synonymous	Exon 32 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.6477C>T	p.Leu2159Leu	synonymous	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.6477C>T	p.Leu2159Leu	synonymous	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.6486C>T	p.Leu2162Leu	synonymous	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000518 AC: 8 AN: 154302 AF XY: 0.0000601

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000837 AC: 115 AN: 1373438 Hom.: 0 Cov.: 35 AF XY: 0.0000682 AC XY: 46 AN XY: 674966

African (AFR) AF: 0.00 AC: 0 AN: 30652

American (AMR) AF: 0.00 AC: 0 AN: 31214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20370

East Asian (EAS) AF: 0.00 AC: 0 AN: 38608

South Asian (SAS) AF: 0.00 AC: 0 AN: 71958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5332

European-Non Finnish (NFE) AF: 0.000104 AC: 111 AN: 1071752

Other (OTH) AF: 0.0000709 AC: 4 AN: 56450

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74244

African (AFR) AF: 0.0000242 AC: 1 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Kabuki syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.9
DANN	Benign	0.76
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs774164988; hg19: chr12-49435076;