rs28522267

Positions:

• chr7-152229936-C-A
• chr7-152229936-C-G
• chr7-152229936-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP2 PP3 BP4_Strong BP6_Moderate

The NM_170606.3(KMT2C):​c.2963G>T​(p.Cys988Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (0 hom., cov: 42)
  • Exomes 𝑓: 0.49 (39 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.90

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2C. . Gene score misZ 2.1357 (greater than the threshold 3.09). Trascript score misZ 4.2875 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, Kleefstra syndrome 2.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.008740902).
• BP6: Variant 7-152229936-C-A is Benign according to our data. Variant chr7-152229936-C-A is described in ClinVar as [Benign]. Clinvar id is 403019.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.2963G>T	p.Cys988Phe	missense_variant	18/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.2963G>T	p.Cys988Phe	missense_variant	18/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 46723 AN: 108170 Hom.: 0 Cov.: 42 FAILED QC

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.343

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.404

GnomAD3 exomes AF: 0.198 AC: 27538 AN: 139298 Hom.: 0 AF XY: 0.177 AC XY: 13344 AN XY: 75550

Gnomad AFR exome AF: 0.161

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.119

Gnomad FIN exome AF: 0.303

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.237

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.488 AC: 634391 AN: 1300290 Hom.: 39 Cov.: 31 AF XY: 0.488 AC XY: 315602 AN XY: 647150

Gnomad4 AFR exome AF: 0.468

Gnomad4 AMR exome AF: 0.485

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.469

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.478

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.432 AC: 46735 AN: 108214 Hom.: 0 Cov.: 42 AF XY: 0.431 AC XY: 23365 AN XY: 54184

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.457

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.403

Alfa AF: 0.361 Hom.: 6

ExAC AF: 0.105 AC: 12517

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-9.0	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.84
MPC		2.9
ClinPred		0.055	T
GERP RS		4.7
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28522267; hg19: chr7-151927021; COSMIC: COSV51275056;