rs200681496

Variant names:

• chr12-49040869-G-A
• rs200681496
• NM_003482.4:c.6901C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49040869-G-A
• chr12-49040869-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000301067.12(KMT2D):​c.6901C>T​(p.Pro2301Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P2301L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: KMT2D ENST00000301067.12 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.525
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16936988).
• BP6: Variant 12-49040869-G-A is Benign according to our data. Variant chr12-49040869-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 134691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000629 (92/1461568) while in subpopulation AFR AF = 0.000717 (24/33478). AF 95% confidence interval is 0.000493. There are 0 homozygotes in GnomAdExome4. There are 44 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000301067.12. 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.6901C>T	p.Pro2301Ser	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.6901C>T	p.Pro2301Ser	missense	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.6901C>T	p.Pro2301Ser	missense	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.6910C>T	p.Pro2304Ser	missense	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000603 AC: 15 AN: 248740 AF XY: 0.0000518

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000629 AC: 92 AN: 1461568 Hom.: 0 Cov.: 35 AF XY: 0.0000605 AC XY: 44 AN XY: 727084

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53390

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111780

Other (OTH) AF: 0.000282 AC: 17 AN: 60370

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74420

African (AFR) AF: 0.000433 AC: 18 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000801 AC: 3

ESP6500EA AF: 0.000367 AC: 3

ExAC AF: 0.0000579 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.069	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	0.045	D
MutationAssessor	Benign	0.55	N
PhyloP100		0.53
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.35
Sift	Benign	0.12	T
Polyphen		0.91	P
Vest4		0.33
MVP		0.36
MPC		0.55
ClinPred		0.057	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.099
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200681496; hg19: chr12-49434652; COSMIC: COSV99979423; COSMIC: COSV99979423;