11-67418914-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001166222.2(CARNS1):​c.523T>A​(p.Phe175Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,591,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CARNS1
NM_001166222.2 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.37698472).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CARNS1NM_001166222.2 linkc.523T>A p.Phe175Ile 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.523T>A p.Phe175Ile missense_variant Exon 5 of 10 NM_001166222.2 ENSP00000510668.1 A5YM72-5

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000176
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
19
AN:
207654
Hom.:
0
AF XY:
0.0000794
AC XY:
9
AN XY:
113280
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000651
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000177
Gnomad OTH exome
AF:
0.000190
GnomAD4 exome
AF:
0.000206
AC:
296
AN:
1438848
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
125
AN XY:
713926
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.0000239
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:
0.000241
Gnomad4 OTH exome
AF:
0.000488
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000176
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000838
Hom.:
0
Bravo
AF:
0.000125
ExAC
AF:
0.0000835
AC:
10

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.523T>A (p.F175I) alteration is located in exon 5 (coding exon 4) of the CARNS1 gene. This alteration results from a T to A substitution at nucleotide position 523, causing the phenylalanine (F) at amino acid position 175 to be replaced by an isoleucine (I). 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
Uncertain
0.45
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
22
DANN
Uncertain
0.97
DEOGEN2
Benign
0.0098
.;T;.
Eigen
Benign
0.037
Eigen_PC
Benign
0.088
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.38
T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.81
.;L;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.16
Sift
Uncertain
0.0070
D;D;D
Sift4G
Benign
0.075
T;T;T
Polyphen
0.69
.;P;.
Vest4
0.66
MVP
0.40
MPC
0.54
ClinPred
0.057
T
GERP RS
4.1
Varity_R
0.26
gMVP
0.61

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: rs144408240; hg19: chr11-67186385; API