18-46435323-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152470.3(ARK2C):​c.412C>T​(p.Arg138Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ARK2C
NM_152470.3 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.75
Variant links:
Genes affected
ARK2C (HGNC:31696): (arkadia (RNF111) C-terminal like ring finger ubiquitin ligase 2C) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in motor neuron axon guidance and positive regulation of BMP signaling pathway. Predicted to act upstream of or within several processes, including forelimb morphogenesis; multicellular organism aging; and nervous system development. Predicted to be part of protein-containing complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARK2CNM_152470.3 linkc.412C>T p.Arg138Cys missense_variant Exon 3 of 8 ENST00000269439.12 NP_689683.2
ARK2CXM_011526016.4 linkc.412C>T p.Arg138Cys missense_variant Exon 3 of 7 XP_011524318.1
ARK2CXM_017025788.3 linkc.412C>T p.Arg138Cys missense_variant Exon 3 of 4 XP_016881277.1
ARK2CNM_001256758.1 linkc.-91-12240C>T intron_variant Intron 1 of 5 NP_001243687.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNF165ENST00000269439.12 linkc.412C>T p.Arg138Cys missense_variant Exon 3 of 8 2 NM_152470.3 ENSP00000269439.6 Q6ZSG1-1
RNF165ENST00000593230.5 linkc.211C>T p.Arg71Cys missense_variant Exon 3 of 5 3 ENSP00000467730.1 K7EQ96
RNF165ENST00000543885.2 linkc.-91-12240C>T intron_variant Intron 1 of 5 2 ENSP00000444285.1 Q6ZSG1-2
RNF165ENST00000586604.5 linkn.62-12240C>T intron_variant Intron 1 of 5 2 ENSP00000468365.1 K7EIS4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251454
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461870
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 26, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.412C>T (p.R138C) alteration is located in exon 3 (coding exon 3) of the RNF165 gene. This alteration results from a C to T substitution at nucleotide position 412, causing the arginine (R) at amino acid position 138 to be replaced by a cysteine (C). 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
0.15
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Uncertain
0.010
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.11
.;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.49
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.4
.;M
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-2.6
.;D
REVEL
Benign
0.21
Sift
Uncertain
0.0010
.;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
.;D
Vest4
0.93
MutPred
0.37
.;Loss of MoRF binding (P = 0.0154);
MVP
0.26
MPC
1.6
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.28
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs752024290; hg19: chr18-44015286; COSMIC: COSV99491740; API