rs28522267

chr7-152229936-C-Achr7-152229936-C-Gchr7-152229936-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PP2 PP3 BP4_Strong BP6_Moderate BS2

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2C
• 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.
• BS2: High AC in GnomAdExome at 27538 AD gene.

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
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;