12-49041141-G-T

Variant names:

• chr12-49041141-G-T
• rs201190869
• NM_003482.4:c.6629C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003482.4(KMT2D):​c.6629C>A​(p.Pro2210Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 1,525,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2210S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 8 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12801632).

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.6629C>A	p.Pro2210Gln	missense	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.6629C>A	p.Pro2210Gln	missense	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.6629C>A	p.Pro2210Gln	missense	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.6638C>A	p.Pro2213Gln	missense	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1372992 Hom.: 0 Cov.: 35 AF XY: 0.00000297 AC XY: 2 AN XY: 674522

African (AFR) AF: 0.00 AC: 0 AN: 30286

American (AMR) AF: 0.00 AC: 0 AN: 29296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39050

South Asian (SAS) AF: 0.00 AC: 0 AN: 70604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1072196

Other (OTH) AF: 0.00 AC: 0 AN: 56412

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41408

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

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

Alfa AF: 0.0000221 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.46
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Polyphen		0.43	B
Vest4		0.13
MutPred		0.25		Loss of loop (P = 0.0203)
MVP		0.22
MPC		0.16
ClinPred		0.18	T
GERP RS		3.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.040
gMVP		0.18
Mutation Taster		=89/11	polymorphism

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: rs201190869; hg19: chr12-49434924;