12-49051745-G-T

Variant names:

• chr12-49051745-G-T
• rs147212187
• NM_003482.4:c.1938C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_003482.4(KMT2D):​c.1938C>A​(p.Pro646Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,413,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P646P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BS2: High AC in GnomAdExome4 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.1938C>A	p.Pro646Pro	synonymous	Exon 11 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.1938C>A	p.Pro646Pro	synonymous	Exon 11 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.1938C>A	p.Pro646Pro	synonymous	Exon 11 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.1938C>A	p.Pro646Pro	synonymous	Exon 10 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.00000736 AC: 1 AN: 135950 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1413362 Hom.: 0 Cov.: 35 AF XY: 0.00000284 AC XY: 2 AN XY: 703820

African (AFR) AF: 0.00 AC: 0 AN: 32466

American (AMR) AF: 0.00 AC: 0 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 38808

South Asian (SAS) AF: 0.00 AC: 0 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000467 AC: 5 AN: 1070510

Other (OTH) AF: 0.0000172 AC: 1 AN: 58280

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000735 AC: 1 AN: 136056 Hom.: 0 Cov.: 28 AF XY: 0.0000151 AC XY: 1 AN XY: 66166

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000277 AC: 1 AN: 36062

American (AMR) AF: 0.00 AC: 0 AN: 13404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3292

East Asian (EAS) AF: 0.00 AC: 0 AN: 4442

South Asian (SAS) AF: 0.00 AC: 0 AN: 4150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 204

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63018

Other (OTH) AF: 0.00 AC: 0 AN: 1880

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.38
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5

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: rs147212187; hg19: chr12-49445528;