rs587778463

Positions:

• chr12-49041378-G-A
• chr12-49041378-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003482.4(KMT2D):​c.6392C>T​(p.Thr2131Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000438 in 1,598,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. T2131N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.19

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.16530502).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.6392C>T	p.Thr2131Ile	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.6392C>T	p.Thr2131Ile	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000447 AC: 1 AN: 223914 Hom.: 0 AF XY: 0.00000815 AC XY: 1 AN XY: 122702

Gnomad AFR exome AF: 0.0000741

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1446274 Hom.: 0 Cov.: 34 AF XY: 0.00000557 AC XY: 4 AN XY: 718592

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000453

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.58	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.025	D
Polyphen		0.041	B
Vest4		0.17
MutPred		0.22		Loss of catalytic residue at T2131 (P = 0.0055);
MVP		0.15
MPC		0.53
ClinPred		0.22	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778463; hg19: chr12-49435161;