chr12-49022263-TC-T

Variant names:

• chr12-49022263-TC-T
• rs34546217
• NM_003482.4:c.16412+16delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003482.4(KMT2D):​c.16412+16delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,602,132 control chromosomes in the GnomAD database, including 96,375 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6630 hom., cov: 23)
  • Exomes 𝑓: 0.35 (89745 hom.)
• Consequence: KMT2D NM_003482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.832
• Publications: 10 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

ENSG00000288710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-49022263-TC-T is Benign according to our data. Variant chr12-49022263-TC-T is described in ClinVar as Benign. ClinVar VariationId is 94193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

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.16412+16delG		intron	N/A	NP_003473.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.16412+16delG		intron	N/A	ENSP00000301067.7
	ENSG00000288710	ENST00000683988.1		n.383+16delG		intron	N/A	ENSP00000506939.1
	KMT2D	ENST00000683543.2		c.16460+16delG		intron	N/A	ENSP00000506726.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40444 AN: 151964 Hom.: 6631 Cov.: 23

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.261

GnomAD2 exomes AF: 0.320 AC: 79303 AN: 247488 AF XY: 0.331

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.435

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.343

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.346 AC: 501016 AN: 1450050 Hom.: 89745 Cov.: 0 AF XY: 0.347 AC XY: 249913 AN XY: 719228

African (AFR) AF: 0.0577 AC: 1924 AN: 33338

American (AMR) AF: 0.232 AC: 10306 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6037 AN: 26018

East Asian (EAS) AF: 0.397 AC: 15617 AN: 39372

South Asian (SAS) AF: 0.395 AC: 33972 AN: 85996

European-Finnish (FIN) AF: 0.365 AC: 19452 AN: 53266

Middle Eastern (MID) AF: 0.229 AC: 1315 AN: 5742

European-Non Finnish (NFE) AF: 0.356 AC: 392510 AN: 1101994

Other (OTH) AF: 0.332 AC: 19883 AN: 59840

GnomAD4 genome AF: 0.266 AC: 40448 AN: 152082 Hom.: 6630 Cov.: 23 AF XY: 0.269 AC XY: 19997 AN XY: 74324

African (AFR) AF: 0.0755 AC: 3133 AN: 41520

American (AMR) AF: 0.257 AC: 3926 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3472

East Asian (EAS) AF: 0.424 AC: 2194 AN: 5178

South Asian (SAS) AF: 0.423 AC: 2038 AN: 4814

European-Finnish (FIN) AF: 0.358 AC: 3778 AN: 10566

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23708 AN: 67940

Other (OTH) AF: 0.261 AC: 549 AN: 2106

Alfa AF: 0.293 Hom.: 1291

Bravo AF: 0.246

Asia WGS AF: 0.387 AC: 1344 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Kabuki syndrome (1)
-	-	1	Kabuki syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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: rs34546217; hg19: chr12-49416046; COSMIC: COSV56407652;