rs28522267

Variant names:

• chr7-152229936-C-A
• rs28522267
• NM_170606.3:c.2963G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP4_Strong BP6_Very_Strong

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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.90
• Publications: 39 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: Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics, Broad Center for Mendelian Genomics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, 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 VariationId is 403019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2C	NM_170606.3	c.2963G>T	p.Cys988Phe	missense_variant	Exon 18 of 59	ENST00000262189.11	NP_733751.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11	c.2963G>T	p.Cys988Phe	missense_variant	Exon 18 of 59	1	NM_170606.3	ENSP00000262189.6

Frequencies

GnomAD3 genomes AF: 0.432 AC: 46723 AN: 108170 Hom.: 0 Cov.: 42

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

GnomAD2 exomes AF: 0.198 AC: 27538 AN: 139298 AF XY: 0.177

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 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

African (AFR) AF: 0.468 AC: 12567 AN: 26874

American (AMR) AF: 0.485 AC: 18887 AN: 38962

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 9973 AN: 21292

East Asian (EAS) AF: 0.469 AC: 14135 AN: 30134

South Asian (SAS) AF: 0.492 AC: 38529 AN: 78332

European-Finnish (FIN) AF: 0.479 AC: 21993 AN: 45960

Middle Eastern (MID) AF: 0.469 AC: 1594 AN: 3400

European-Non Finnish (NFE) AF: 0.490 AC: 492288 AN: 1004250

Other (OTH) AF: 0.478 AC: 24425 AN: 51086

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

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

African (AFR) AF: 0.405 AC: 10806 AN: 26694

American (AMR) AF: 0.404 AC: 4250 AN: 10532

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1094 AN: 2396

East Asian (EAS) AF: 0.343 AC: 1253 AN: 3650

South Asian (SAS) AF: 0.368 AC: 1218 AN: 3310

European-Finnish (FIN) AF: 0.421 AC: 3226 AN: 7670

Middle Eastern (MID) AF: 0.144 AC: 28 AN: 194

European-Non Finnish (NFE) AF: 0.464 AC: 23872 AN: 51460

Other (OTH) AF: 0.403 AC: 647 AN: 1606

⚠️ 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: 0.361 Hom.: 6

ExAC AF: 0.105 AC: 12517

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		7.9
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
Mutation Taster		=33/67	disease causing

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

Other links and lift over

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