rs6464211

Variant names:

• chr7-152176768-C-T
• rs6464211
• NM_170606.3:c.8685G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_170606.3(KMT2C):​c.8685G>A​(p.Gln2895Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,613,820 control chromosomes in the GnomAD database, including 44,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (12309 hom., cov: 32)
  • Exomes 𝑓: 0.18 (31862 hom.)
• Consequence: KMT2C NM_170606.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.403
• Publications: 30 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.04).
• BP6: Variant 7-152176768-C-T is Benign according to our data. Variant chr7-152176768-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.403 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

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.8685G>A	p.Gln2895Gln	synonymous	Exon 38 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.8685G>A	p.Gln2895Gln	synonymous	Exon 38 of 59	ENSP00000262189.6	Q8NEZ4-1
	KMT2C	ENST00000360104.8	TSL:1	c.4305G>A	p.Gln1435Gln	synonymous	Exon 10 of 31	ENSP00000353218.4	H7BY37
	KMT2C	ENST00000473186.5	TSL:1	n.6396G>A		non_coding_transcript_exon	Exon 24 of 46

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50265 AN: 151946 Hom.: 12273 Cov.: 32

Gnomad AFR AF: 0.694

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.242 AC: 60619 AN: 250782 AF XY: 0.231

Gnomad AFR exome AF: 0.702

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.318

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.184 AC: 268976 AN: 1461756 Hom.: 31862 Cov.: 36 AF XY: 0.185 AC XY: 134771 AN XY: 727168

African (AFR) AF: 0.715 AC: 23951 AN: 33480

American (AMR) AF: 0.233 AC: 10440 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 6219 AN: 26136

East Asian (EAS) AF: 0.303 AC: 12044 AN: 39692

South Asian (SAS) AF: 0.264 AC: 22779 AN: 86254

European-Finnish (FIN) AF: 0.264 AC: 14104 AN: 53398

Middle Eastern (MID) AF: 0.248 AC: 1431 AN: 5768

European-Non Finnish (NFE) AF: 0.148 AC: 164913 AN: 1111912

Other (OTH) AF: 0.217 AC: 13095 AN: 60394

GnomAD4 genome AF: 0.331 AC: 50357 AN: 152064 Hom.: 12309 Cov.: 32 AF XY: 0.333 AC XY: 24787 AN XY: 74340

African (AFR) AF: 0.694 AC: 28772 AN: 41466

American (AMR) AF: 0.231 AC: 3534 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 837 AN: 3470

East Asian (EAS) AF: 0.307 AC: 1584 AN: 5160

South Asian (SAS) AF: 0.272 AC: 1312 AN: 4828

European-Finnish (FIN) AF: 0.277 AC: 2926 AN: 10560

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10645 AN: 67988

Other (OTH) AF: 0.295 AC: 620 AN: 2102

Alfa AF: 0.218 Hom.: 20112

Bravo AF: 0.343

Asia WGS AF: 0.323 AC: 1120 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Kleefstra syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.023
DANN	Benign	0.20
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs6464211; hg19: chr7-151873853; COSMIC: COSV51370950; COSMIC: COSV51370950;