3-12570082-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014160.5(MKRN2):​c.167C>T​(p.Thr56Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,458,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T56K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

MKRN2
NM_014160.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.105

Publications

1 publications found
Variant links:
Genes affected
MKRN2 (HGNC:7113): (makorin ring finger protein 2) This gene encodes a probable E3 ubiquitin ligase containing several zinc finger domains, that is a member of the makorin RING zinc-finger protein family. This gene overlaps the v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) gene in an antisense orientation and may have a co-regulatory function with RAF1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1953842).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MKRN2NM_014160.5 linkc.167C>T p.Thr56Met missense_variant Exon 3 of 8 ENST00000170447.12 NP_054879.3
MKRN2NM_001271707.2 linkc.38C>T p.Thr13Met missense_variant Exon 2 of 7 NP_001258636.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MKRN2ENST00000170447.12 linkc.167C>T p.Thr56Met missense_variant Exon 3 of 8 1 NM_014160.5 ENSP00000170447.7 Q9H000-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.0000121
AC:
3
AN:
248102
AF XY:
0.0000223
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1458380
Hom.:
0
Cov.:
30
AF XY:
0.0000124
AC XY:
9
AN XY:
725584
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33322
American (AMR)
AF:
0.00
AC:
0
AN:
43972
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25888
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86010
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52792
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5644
European-Non Finnish (NFE)
AF:
0.0000135
AC:
15
AN:
1110850
Other (OTH)
AF:
0.00
AC:
0
AN:
60220
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000309
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 31, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.167C>T (p.T56M) alteration is located in exon 3 (coding exon 3) of the MKRN2 gene. This alteration results from a C to T substitution at nucleotide position 167, causing the threonine (T) at amino acid position 56 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.067
T;.;.
Eigen
Benign
-0.44
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.85
D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.3
M;.;.
PhyloP100
0.10
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.72
N;N;N
REVEL
Benign
0.015
Sift
Benign
0.054
T;D;T
Sift4G
Benign
0.13
T;T;T
Polyphen
0.25
B;.;B
Vest4
0.26
MutPred
0.40
Loss of sheet (P = 0.0457);.;.;
MVP
0.48
MPC
0.28
ClinPred
0.37
T
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.026
gMVP
0.31
Mutation Taster
=78/22
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs773116580; hg19: chr3-12611581; API