2-202942858-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024744.17(CARF):​c.197C>T​(p.Pro66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CARF
NM_024744.17 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76
Variant links:
Genes affected
CARF (HGNC:14435): (calcium responsive transcription factor) Enables DNA binding activity and DNA-binding transcription factor activity. Involved in cellular response to potassium ion and positive regulation of transcription from RNA polymerase II promoter in response to calcium ion. Predicted to be located in granular component. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]
WDR12 (HGNC:14098): (WD repeat domain 12) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein is highly similar to the mouse WD repeat domain 12 protein at the amino acid level. The protein encoded by this gene is a component of a nucleolar protein complex that affects maturation of the large ribosomal subunit.[provided by RefSeq, Dec 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07227105).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CARFNM_024744.17 linkc.197C>T p.Pro66Leu missense_variant Exon 5 of 17 ENST00000438828.4 NP_079020.13 Q8N187-1A0A024R405

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CARFENST00000438828.4 linkc.197C>T p.Pro66Leu missense_variant Exon 5 of 17 1 NM_024744.17 ENSP00000414644.1 Q8N187-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249268
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135214
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
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:
0.00000205
AC:
3
AN:
1461842
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000828
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.197C>T (p.P66L) alteration is located in exon 5 (coding exon 2) of the CARF gene. This alteration results from a C to T substitution at nucleotide position 197, causing the proline (P) at amino acid position 66 to be replaced by a leucine (L). 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
0.076
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
13
DANN
Benign
0.97
DEOGEN2
Benign
0.098
T;.;.;.;.;.;.;.;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.83
.;T;T;T;T;T;T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.072
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;.;.;.;.;.;.;.;L
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-0.40
N;N;N;N;D;D;D;D;N
REVEL
Benign
0.086
Sift
Benign
0.11
T;T;T;T;D;D;D;T;T
Sift4G
Benign
0.11
T;T;T;T;D;T;T;T;T
Polyphen
0.078
B;.;B;.;.;.;.;.;B
Vest4
0.11
MutPred
0.26
Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);.;Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);
MVP
0.14
MPC
0.23
ClinPred
0.13
T
GERP RS
4.7
Varity_R
0.040
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs765919935; hg19: chr2-203807581; API