rs111305262

Variant names:

• chr12-49040582-A-G
• rs111305262
• NM_003482.4:c.7188T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-49040582-A-G
• chr12-49040582-A-C
• chr12-49040582-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003482.4(KMT2D):​c.7188T>C​(p.Cys2396Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,274 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (63 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0920
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, ClinGen
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-49040582-A-G is Benign according to our data. Variant chr12-49040582-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.7188T>C	p.Cys2396Cys	synonymous	Exon 32 of 55	NP_003473.3	O14686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.7188T>C	p.Cys2396Cys	synonymous	Exon 32 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.7188T>C	p.Cys2396Cys	synonymous	Exon 32 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.7197T>C	p.Cys2399Cys	synonymous	Exon 31 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2426 AN: 151886 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00402 AC: 992 AN: 246998 AF XY: 0.00273

Gnomad AFR exome AF: 0.0557

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000607

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00162 AC: 2363 AN: 1461270 Hom.: 63 Cov.: 35 AF XY: 0.00142 AC XY: 1029 AN XY: 726906

African (AFR) AF: 0.0551 AC: 1845 AN: 33474

American (AMR) AF: 0.00378 AC: 169 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86226

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53334

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1111684

Other (OTH) AF: 0.00333 AC: 201 AN: 60348

GnomAD4 genome AF: 0.0160 AC: 2435 AN: 152004 Hom.: 71 Cov.: 32 AF XY: 0.0151 AC XY: 1120 AN XY: 74308

African (AFR) AF: 0.0549 AC: 2274 AN: 41402

American (AMR) AF: 0.00772 AC: 118 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67948

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00884 Hom.: 15

Bravo AF: 0.0181

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Kabuki syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.0
DANN	Benign	0.61
PhyloP100		0.092
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111305262; hg19: chr12-49434365; COSMIC: COSV56422169;