chr7-152177607-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_170606.3(KMT2C):​c.7846C>T​(p.Pro2616Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

1
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2O:1

Conservation

PhyloP100: 0.470
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.043851525).
BP6
Variant 7-152177607-G-A is Benign according to our data. Variant chr7-152177607-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-152177607-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000171 (25/1461882) while in subpopulation AFR AF= 0.000508 (17/33480). AF 95% confidence interval is 0.000323. There are 0 homozygotes in gnomad4_exome. There are 14 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2CNM_170606.3 linkc.7846C>T p.Pro2616Ser missense_variant 38/59 ENST00000262189.11 NP_733751.2 Q8NEZ4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2CENST00000262189.11 linkc.7846C>T p.Pro2616Ser missense_variant 38/591 NM_170606.3 ENSP00000262189.6 Q8NEZ4-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152172
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251356
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461882
Hom.:
0
Cov.:
35
AF XY:
0.0000193
AC XY:
14
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152290
Hom.:
0
Cov.:
31
AF XY:
0.000121
AC XY:
9
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000175
Hom.:
0
Bravo
AF:
0.000144
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsOct 20, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024- -
not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
15
DANN
Benign
0.57
DEOGEN2
Benign
0.14
T;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.20
N
LIST_S2
Benign
0.77
.;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.044
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Benign
0.070
Sift
Benign
0.080
T;T
Polyphen
0.0030
B;B
Vest4
0.090
MVP
0.32
MPC
0.079
ClinPred
0.064
T
GERP RS
0.23
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.090
gMVP
0.43

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142938767; hg19: chr7-151874692; COSMIC: COSV51441901; COSMIC: COSV51441901; API