3-12572251-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_014160.5(MKRN2):​c.520G>C​(p.Ala174Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A174T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MKRN2
NM_014160.5 missense

Scores

6
10
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.34

Publications

0 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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MKRN2NM_014160.5 linkc.520G>C p.Ala174Pro missense_variant Exon 4 of 8 ENST00000170447.12 NP_054879.3
MKRN2NM_001271707.2 linkc.391G>C p.Ala131Pro missense_variant Exon 3 of 7 NP_001258636.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MKRN2ENST00000170447.12 linkc.520G>C p.Ala174Pro missense_variant Exon 4 of 8 1 NM_014160.5 ENSP00000170447.7 Q9H000-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461858
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727234
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
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.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T;.;.
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.048
D
MetaRNN
Pathogenic
0.82
D;D;D
MetaSVM
Benign
-0.43
T
MutationAssessor
Pathogenic
3.6
H;.;.
PhyloP100
7.3
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-4.4
D;D;D
REVEL
Uncertain
0.37
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.021
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.82
MutPred
0.56
Loss of catalytic residue at A174 (P = 0.0549);.;.;
MVP
0.78
MPC
0.90
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.86
gMVP
0.82
Mutation Taster
=56/44
polymorphism

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

Other links and lift over

dbSNP: rs748431588; hg19: chr3-12613750; API