chr12-49048778-CAG-C

Variant names:

• chr12-49048778-CAG-C
• rs55776244
• NM_003482.4:c.4021-11_4021-10delCT

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.4021-11_4021-10delCT variant causes a intron change. The variant allele was found at a frequency of 0.0335 in 1,562,362 control chromosomes in the GnomAD database, including 1,417 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (451 hom., cov: 32)
  • Exomes 𝑓: 0.031 (966 hom.)
• Consequence: KMT2D NM_003482.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.66
• Publications: 5 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 -16 ACMG points.

• BP6: Variant 12-49048778-CAG-C is Benign according to our data. Variant chr12-49048778-CAG-C is described in ClinVar as Benign. ClinVar VariationId is 94214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.4021-11_4021-10delCT		intron_variant	Intron 13 of 54	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.4021-11_4021-10delCT		intron_variant	Intron 13 of 54	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 9249 AN: 152168 Hom.: 447 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0542

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.0530

GnomAD2 exomes AF: 0.0352 AC: 8583 AN: 243616 AF XY: 0.0334

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0476

Gnomad NFE exome AF: 0.0324

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0306 AC: 43129 AN: 1410076 Hom.: 966 AF XY: 0.0301 AC XY: 21100 AN XY: 701784

African (AFR) AF: 0.135 AC: 4377 AN: 32446

American (AMR) AF: 0.0254 AC: 1123 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 653 AN: 25600

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39260

South Asian (SAS) AF: 0.0251 AC: 2129 AN: 84822

European-Finnish (FIN) AF: 0.0460 AC: 2294 AN: 49846

Middle Eastern (MID) AF: 0.0332 AC: 187 AN: 5626

European-Non Finnish (NFE) AF: 0.0284 AC: 30391 AN: 1069662

Other (OTH) AF: 0.0337 AC: 1970 AN: 58542

GnomAD4 genome AF: 0.0609 AC: 9277 AN: 152286 Hom.: 451 Cov.: 32 AF XY: 0.0595 AC XY: 4429 AN XY: 74460

African (AFR) AF: 0.130 AC: 5401 AN: 41540

American (AMR) AF: 0.0381 AC: 583 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4830

European-Finnish (FIN) AF: 0.0542 AC: 575 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0349 AC: 2375 AN: 68032

Other (OTH) AF: 0.0525 AC: 111 AN: 2116

Alfa AF: 0.0497 Hom.: 55

Bravo AF: 0.0616

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55776244; hg19: chr12-49442561;