11-67419118-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001166222.2(CARNS1):​c.727C>T​(p.Arg243Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,573,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

CARNS1
NM_001166222.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.119
Variant links:
Genes affected
CARNS1 (HGNC:29268): (carnosine synthase 1) CARNS1 (EC 6.3.2.11), a member of the ATP-grasp family of ATPases, catalyzes the formation of carnosine (beta-alanyl-L-histidine) and homocarnosine (gamma-aminobutyryl-L-histidine), which are found mainly in skeletal muscle and the central nervous system, respectively (Drozak et al., 2010 [PubMed 20097752]).[supplied by OMIM, Apr 2010]
PPP1CA (HGNC:9281): (protein phosphatase 1 catalytic subunit alpha) The protein encoded by this gene is one of the three catalytic subunits of protein phosphatase 1 (PP1). This broadly expressed gene encodes the alpha subunit of the PP1 complex that associates with over 200 regulatory proteins to form holoenzymes which dephosphorylate their biological targets with high specificity. PP1 is a serine/threonine specific protein phosphatase known to be involved in the regulation of a variety of cellular processes, such as cell division, glycogen metabolism, muscle contractility, protein synthesis, and HIV-1 viral transcription. Increased PP1 activity has been observed in the end stage of heart failure. Studies suggest that PP1 is an important regulator of cardiac function and that PP1 deregulation is implicated in diabetes and multiple types of cancer. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03242886).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CARNS1NM_001166222.2 linkc.727C>T p.Arg243Trp missense_variant Exon 5 of 10 ENST00000687366.1 NP_001159694.1 A5YM72-5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CARNS1ENST00000687366.1 linkc.727C>T p.Arg243Trp missense_variant Exon 5 of 10 NM_001166222.2 ENSP00000510668.1 A5YM72-5

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152080
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000217
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000520
AC:
10
AN:
192160
Hom.:
0
AF XY:
0.0000669
AC XY:
7
AN XY:
104664
show subpopulations
Gnomad AFR exome
AF:
0.0000993
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000338
Gnomad EAS exome
AF:
0.000345
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000200
GnomAD4 exome
AF:
0.0000127
AC:
18
AN:
1420932
Hom.:
0
Cov.:
32
AF XY:
0.0000157
AC XY:
11
AN XY:
701932
show subpopulations
Gnomad4 AFR exome
AF:
0.0000915
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000157
Gnomad4 EAS exome
AF:
0.000105
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000459
Gnomad4 OTH exome
AF:
0.0000170
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152198
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000826
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000339
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.727C>T (p.R243W) alteration is located in exon 5 (coding exon 4) of the CARNS1 gene. This alteration results from a C to T substitution at nucleotide position 727, causing the arginine (R) at amino acid position 243 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
Benign
0.083
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0057
.;T;.
Eigen
Benign
-0.99
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.77
T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.032
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
.;L;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.047
Sift
Benign
0.063
T;T;T
Sift4G
Uncertain
0.010
D;D;D
Polyphen
0.0
.;B;.
Vest4
0.18
MVP
0.17
MPC
0.10
ClinPred
0.016
T
GERP RS
-0.00031
Varity_R
0.069
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: rs774158852; hg19: chr11-67186589; API