chr12-49052257-C-T

Variant names:

• chr12-49052257-C-T
• rs1064210
• NM_003482.4:c.1426G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003482.4(KMT2D):​c.1426G>A​(p.Ala476Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,478,052 control chromosomes in the GnomAD database, including 3,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1650 hom., cov: 30)
  • Exomes 𝑓: 0.011 (1610 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -2.15
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004093617).
• BP6: Variant 12-49052257-C-T is Benign according to our data. Variant chr12-49052257-C-T is described in ClinVar as Benign. ClinVar VariationId is 94174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 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.1426G>A	p.Ala476Thr	missense	Exon 11 of 55	NP_003473.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.1426G>A	p.Ala476Thr	missense	Exon 11 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.1426G>A	p.Ala476Thr	missense	Exon 11 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.1426G>A	p.Ala476Thr	missense	Exon 10 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0888 AC: 12313 AN: 138598 Hom.: 1636 Cov.: 30

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0435

Gnomad ASJ AF: 0.00431

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0670

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0691

GnomAD2 exomes AF: 0.0277 AC: 5707 AN: 205848 AF XY: 0.0217

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.00406

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0107 AC: 14277 AN: 1339318 Hom.: 1610 Cov.: 37 AF XY: 0.00982 AC XY: 6494 AN XY: 661574

African (AFR) AF: 0.321 AC: 10078 AN: 31362

American (AMR) AF: 0.0231 AC: 815 AN: 35212

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 100 AN: 23040

East Asian (EAS) AF: 0.00 AC: 0 AN: 32598

South Asian (SAS) AF: 0.0167 AC: 1126 AN: 67330

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49028

Middle Eastern (MID) AF: 0.0222 AC: 118 AN: 5314

European-Non Finnish (NFE) AF: 0.000737 AC: 767 AN: 1041316

Other (OTH) AF: 0.0235 AC: 1272 AN: 54118

GnomAD4 genome AF: 0.0892 AC: 12373 AN: 138734 Hom.: 1650 Cov.: 30 AF XY: 0.0860 AC XY: 5802 AN XY: 67490

African (AFR) AF: 0.301 AC: 11485 AN: 38110

American (AMR) AF: 0.0434 AC: 599 AN: 13796

Ashkenazi Jewish (ASJ) AF: 0.00431 AC: 14 AN: 3250

East Asian (EAS) AF: 0.00 AC: 0 AN: 4312

South Asian (SAS) AF: 0.0133 AC: 55 AN: 4120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9414

Middle Eastern (MID) AF: 0.0652 AC: 12 AN: 184

European-Non Finnish (NFE) AF: 0.00126 AC: 79 AN: 62830

Other (OTH) AF: 0.0684 AC: 129 AN: 1886

Alfa AF: 0.0262 Hom.: 1051

Bravo AF: 0.0939

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.274 AC: 1173

ESP6500EA AF: 0.00166 AC: 14

ExAC AF: 0.0279 AC: 3386

Asia WGS AF: 0.0270 AC: 94 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	1	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.38
DANN	Benign	0.47
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Polyphen		0.015	B
Vest4		0.025
MPC		0.18
ClinPred		0.0028	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.042
Mutation Taster		=98/2	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: rs1064210; hg19: chr12-49446040; COSMIC: COSV56457249;