chr12-49041252-G-A

Variant names:

• chr12-49041252-G-A
• rs765654409
• NM_003482.4:c.6518C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_003482.4(KMT2D):​c.6518C>T​(p.Ser2173Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,516,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S2173S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 3.05
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12694305).
• BP6: Variant 12-49041252-G-A is Benign according to our data. Variant chr12-49041252-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 531879.
• BS2: High AC in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.6518C>T	p.Ser2173Leu	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.6518C>T	p.Ser2173Leu	missense	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.6518C>T	p.Ser2173Leu	missense	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.6527C>T	p.Ser2176Leu	missense	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000545 AC: 8 AN: 146918 AF XY: 0.0000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000429

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000315 AC: 43 AN: 1364044 Hom.: 0 Cov.: 35 AF XY: 0.0000344 AC XY: 23 AN XY: 669408

African (AFR) AF: 0.0000331 AC: 1 AN: 30204

American (AMR) AF: 0.0000353 AC: 1 AN: 28334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19788

East Asian (EAS) AF: 0.0000777 AC: 3 AN: 38618

South Asian (SAS) AF: 0.000114 AC: 8 AN: 70006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47236

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5308

European-Non Finnish (NFE) AF: 0.0000271 AC: 29 AN: 1068482

Other (OTH) AF: 0.00 AC: 0 AN: 56068

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74274

African (AFR) AF: 0.0000242 AC: 1 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67978

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000348 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome;CN030661:Kabuki syndrome 1 (1)
-	-	1	Kabuki syndrome (1)
-	1	-	Kabuki syndrome 1 (1)
-	1	-	KMT2D-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.69	N
PhyloP100		3.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Polyphen		0.14	B
Vest4		0.33
MutPred		0.25		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.50
MPC		0.15
ClinPred		0.13	T
GERP RS		4.1
Varity_R		0.15
gMVP		0.16
Mutation Taster		=73/27	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: rs765654409; hg19: chr12-49435035; COSMIC: COSV107371852;