rs182887940

Variant names:

• chr12-49042324-G-A
• rs182887940
• NM_003482.4:c.5874C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49042324-G-A
• chr12-49042324-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000301067.12(KMT2D):​c.5874C>T​(p.Arg1958Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,533,872 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (30 hom.)
• Consequence: KMT2D ENST00000301067.12 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.97
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 12-49042324-G-A is Benign according to our data. Variant chr12-49042324-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0013 (198/152206) while in subpopulation SAS AF = 0.0118 (57/4824). AF 95% confidence interval is 0.00936. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 198 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.5874C>T	p.Arg1958Arg	synonymous	Exon 29 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.5874C>T	p.Arg1958Arg	synonymous	Exon 29 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.5874C>T	p.Arg1958Arg	synonymous	Exon 29 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.5883C>T	p.Arg1961Arg	synonymous	Exon 28 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00377 AC: 543 AN: 144110 AF XY: 0.00492

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00126

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00173 AC: 2397 AN: 1381666 Hom.: 30 Cov.: 33 AF XY: 0.00219 AC XY: 1492 AN XY: 680086

African (AFR) AF: 0.000161 AC: 5 AN: 31014

American (AMR) AF: 0.00111 AC: 37 AN: 33340

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 386 AN: 23610

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36246

South Asian (SAS) AF: 0.0146 AC: 1127 AN: 77446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46278

Middle Eastern (MID) AF: 0.0124 AC: 66 AN: 5344

European-Non Finnish (NFE) AF: 0.000531 AC: 569 AN: 1071384

Other (OTH) AF: 0.00361 AC: 206 AN: 57004

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74430

African (AFR) AF: 0.000169 AC: 7 AN: 41528

American (AMR) AF: 0.00131 AC: 20 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3468

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

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67986

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00393 Hom.: 2

Bravo AF: 0.00105

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Kabuki syndrome (1)
-	-	1	Kabuki syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.67
PhyloP100		2.0
PromoterAI		0.0054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182887940; hg19: chr12-49436107; COSMIC: COSV104396733;