12-49053633-G-C

Variant names:

• chr12-49053633-G-C
• rs201994402
• NM_003482.4:c.682C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003482.4(KMT2D):​c.682C>G​(p.Arg228Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,593,394 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R228C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.10
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, ClinGen
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01942423).
• BP6: Variant 12-49053633-G-C is Benign according to our data. Variant chr12-49053633-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 44 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.682C>G	p.Arg228Gly	missense	Exon 7 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.682C>G	p.Arg228Gly	missense	Exon 7 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.682C>G	p.Arg228Gly	missense	Exon 7 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.682C>G	p.Arg228Gly	missense	Exon 6 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000467 AC: 100 AN: 214098 AF XY: 0.000529

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00902

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000923

GnomAD4 exome AF: 0.000207 AC: 298 AN: 1441230 Hom.: 1 Cov.: 32 AF XY: 0.000215 AC XY: 154 AN XY: 714916

African (AFR) AF: 0.00 AC: 0 AN: 32938

American (AMR) AF: 0.0000481 AC: 2 AN: 41544

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 214 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 38472

South Asian (SAS) AF: 0.00 AC: 0 AN: 82714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000363 AC: 40 AN: 1102528

Other (OTH) AF: 0.000704 AC: 42 AN: 59700

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000359

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.000273 AC: 33

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.069	T
Eigen	Benign	0.00030
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.48
Sift	Benign	0.24	T
Polyphen		0.36	B
Vest4		0.63
MVP		0.43
MPC		0.24
ClinPred		0.039	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.73
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201994402; hg19: chr12-49447416; COSMIC: COSV56467471; COSMIC: COSV56467471;