10-68749624-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_018237.4(CCAR1):​c.1057C>T​(p.Arg353Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CCAR1
NM_018237.4 missense

Scores

4
5
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.71

Publications

3 publications found
Variant links:
Genes affected
CCAR1 (HGNC:24236): (cell division cycle and apoptosis regulator 1) Enables RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; nuclear receptor coactivator activity; and transcription corepressor activity. Involved in positive regulation of cell migration and positive regulation of cell population proliferation. Acts upstream of or within positive regulation of apoptotic process. Located in nuclear envelope lumen. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.31146517).
BS2
High AC in GnomAdExome4 at 86 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CCAR1NM_018237.4 linkc.1057C>T p.Arg353Trp missense_variant Exon 10 of 25 ENST00000265872.11 NP_060707.2 Q8IX12-1
CCAR1NM_001282959.2 linkc.1012C>T p.Arg338Trp missense_variant Exon 9 of 24 NP_001269888.1 Q8IX12-2
CCAR1NM_001282960.2 linkc.1012C>T p.Arg338Trp missense_variant Exon 9 of 24 NP_001269889.1 Q8IX12-2
CCAR1NR_104262.2 linkn.1157C>T non_coding_transcript_exon_variant Exon 10 of 24

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CCAR1ENST00000265872.11 linkc.1057C>T p.Arg353Trp missense_variant Exon 10 of 25 1 NM_018237.4 ENSP00000265872.6 Q8IX12-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000358
AC:
9
AN:
251426
AF XY:
0.0000368
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000588
AC:
86
AN:
1461734
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727176
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39694
South Asian (SAS)
AF:
0.0000696
AC:
6
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53410
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000657
AC:
73
AN:
1111880
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
4
9
13
18
22
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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
AF:
0.0000131
AC:
2
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41428
American (AMR)
AF:
0.00
AC:
0
AN:
15262
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000319
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 08, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1057C>T (p.R353W) alteration is located in exon 10 (coding exon 9) of the CCAR1 gene. This alteration results from a C to T substitution at nucleotide position 1057, causing the arginine (R) at amino acid position 353 to be replaced by a tryptophan (W). 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
Pathogenic
0.97
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.25
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.39
.;T;.;.;.;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.063
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D
M_CAP
Uncertain
0.093
D
MetaRNN
Benign
0.31
T;T;T;T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.97
.;L;.;.;.;.
PhyloP100
2.7
PrimateAI
Pathogenic
0.91
D
PROVEAN
Uncertain
-3.9
.;D;D;D;D;D
REVEL
Benign
0.16
Sift
Uncertain
0.014
.;D;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
0.0010, 1.0, 0.0040
.;B;D;.;B;.
Vest4
0.66
MVP
0.47
MPC
1.9
ClinPred
0.78
D
GERP RS
3.6
Varity_R
0.27
gMVP
0.44
Mutation Taster
=64/36
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: rs143403057; hg19: chr10-70509381; COSMIC: COSV56267681; API