rs150073007

Variant names:

• chr7-152247986-G-GT
• rs150073007
• NM_170606.3:c.2447dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The NM_170606.3(KMT2C):​c.2447dupA​(p.Tyr816fs) variant causes a frameshift, stop gained change. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.49 (0 hom., cov: 0)
  • Exomes 𝑓: 0.49 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2C NM_170606.3 frameshift, stop_gained
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.77
• Publications: 24 publications found

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

KMT2C Gene-Disease associations (from GenCC):

• Kleefstra syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, Broad Center for Mendelian Genomics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 7-152247986-G-GT is Benign according to our data. Variant chr7-152247986-G-GT is described in ClinVar as Benign. ClinVar VariationId is 403020.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170606.3. 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
	KMT2C	NM_170606.3	MANE Select	c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 59	NP_733751.2	Q8NEZ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2C	ENST00000262189.11	TSL:1 MANE Select	c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 59	ENSP00000262189.6	Q8NEZ4-1
	KMT2C	ENST00000682283.1		c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 60	ENSP00000507485.1	Q8NEZ4-3
	KMT2C	ENST00000679882.1		c.2447dupA	p.Tyr816fs	frameshift stop_gained	Exon 14 of 56	ENSP00000506154.1	A0A7P0TAI3

Frequencies

GnomAD3 genomes AF: 0.495 AC: 72119 AN: 145804 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.492

GnomAD2 exomes AF: 0.487 AC: 81747 AN: 167790 AF XY: 0.488

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.498

Gnomad FIN exome AF: 0.490

Gnomad NFE exome AF: 0.485

Gnomad OTH exome AF: 0.478

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.492 AC: 635498 AN: 1292742 Hom.: 0 Cov.: 75 AF XY: 0.492 AC XY: 317601 AN XY: 645684

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

African (AFR) AF: 0.496 AC: 14894 AN: 30056

American (AMR) AF: 0.495 AC: 20393 AN: 41178

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 11352 AN: 23226

East Asian (EAS) AF: 0.500 AC: 19512 AN: 39040

South Asian (SAS) AF: 0.498 AC: 41128 AN: 82504

European-Finnish (FIN) AF: 0.492 AC: 24311 AN: 49462

Middle Eastern (MID) AF: 0.491 AC: 2580 AN: 5256

European-Non Finnish (NFE) AF: 0.490 AC: 474876 AN: 968238

Other (OTH) AF: 0.492 AC: 26452 AN: 53782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.495 AC: 72179 AN: 145924 Hom.: 0 Cov.: 0 AF XY: 0.495 AC XY: 35339 AN XY: 71454

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

African (AFR) AF: 0.497 AC: 19865 AN: 40008

American (AMR) AF: 0.494 AC: 7276 AN: 14714

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1637 AN: 3318

East Asian (EAS) AF: 0.500 AC: 2534 AN: 5068

South Asian (SAS) AF: 0.498 AC: 2337 AN: 4694

European-Finnish (FIN) AF: 0.493 AC: 4991 AN: 10120

Middle Eastern (MID) AF: 0.489 AC: 134 AN: 274

European-Non Finnish (NFE) AF: 0.493 AC: 31978 AN: 64842

Other (OTH) AF: 0.493 AC: 988 AN: 2006

⚠️ 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: 0.488 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs150073007; hg19: chr7-151945071; COSMIC: COSV51275813;