12-49051743-G-T

Variant names:

• chr12-49051743-G-T
• rs200088180
• NM_003482.4:c.1940C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_003482.4(KMT2D):​c.1940C>A​(p.Pro647Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,585,578 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P647T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00073 (4 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:4
• Conservation: PhyloP100: 1.50
• Publications: 9 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0853588).
• BP6: Variant 12-49051743-G-T is Benign according to our data. Variant chr12-49051743-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94196.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000502 (75/149434) while in subpopulation AMR AF = 0.00153 (23/15060). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 75 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.1940C>A	p.Pro647Gln	missense	Exon 11 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.1940C>A	p.Pro647Gln	missense	Exon 11 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.1940C>A	p.Pro647Gln	missense	Exon 11 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.1940C>A	p.Pro647Gln	missense	Exon 10 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.000496 AC: 74 AN: 149314 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000426

Gnomad FIN AF: 0.000289

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000536

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000465 AC: 114 AN: 245350 AF XY: 0.000542

Gnomad AFR exome AF: 0.000326

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.000671

GnomAD4 exome AF: 0.000734 AC: 1054 AN: 1436144 Hom.: 4 Cov.: 35 AF XY: 0.000759 AC XY: 542 AN XY: 714306

African (AFR) AF: 0.000363 AC: 12 AN: 33048

American (AMR) AF: 0.000315 AC: 14 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.000993 AC: 85 AN: 85578

European-Finnish (FIN) AF: 0.000416 AC: 22 AN: 52942

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5716

European-Non Finnish (NFE) AF: 0.000787 AC: 858 AN: 1089972

Other (OTH) AF: 0.000893 AC: 53 AN: 59374

GnomAD4 genome AF: 0.000502 AC: 75 AN: 149434 Hom.: 0 Cov.: 28 AF XY: 0.000507 AC XY: 37 AN XY: 73010

African (AFR) AF: 0.000247 AC: 10 AN: 40452

American (AMR) AF: 0.00153 AC: 23 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5018

South Asian (SAS) AF: 0.000639 AC: 3 AN: 4694

European-Finnish (FIN) AF: 0.000289 AC: 3 AN: 10392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000536 AC: 36 AN: 67126

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.000604 Hom.: 1

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.000594 AC: 5

ExAC AF: 0.000405 AC: 49

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
1	1	-	Kabuki syndrome 1 (2)
-	-	1	Kabuki syndrome (1)
-	-	1	KMT2D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.50
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.44
Sift	Benign	0.11	T
Polyphen		0.85	P
Vest4		0.39
MVP		0.82
MPC		0.17
ClinPred		0.017	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.043
gMVP		0.33
Mutation Taster		=97/3	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: rs200088180; hg19: chr12-49445526; COSMIC: COSV99040251; COSMIC: COSV99040251;