2-202952595-C-A

Variant names:

• chr2-202952595-C-A
• NM_024744.17:c.343C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024744.17(CARF):​c.343C>A​(p.Leu115Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,614 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: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CARF NM_024744.17 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

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=0.23008311).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARF	NM_024744.17	c.343C>A	p.Leu115Ile	missense_variant	Exon 6 of 17	ENST00000438828.4	NP_079020.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARF	ENST00000438828.4	c.343C>A	p.Leu115Ile	missense_variant	Exon 6 of 17	1	NM_024744.17	ENSP00000414644.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461614 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343C>A (p.L115I) alteration is located in exon 6 (coding exon 3) of the CARF gene. This alteration results from a C to A substitution at nucleotide position 343, causing the leucine (L) at amino acid position 115 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	Benign	0.12
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	.;T;T;D;D;D;.;D;D;D
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.;.;.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.34	N;.;N;N;N;N;N;N;N;N
REVEL	Benign	0.094
Sift	Uncertain	0.023	D;.;D;D;D;D;T;D;D;D
Sift4G	Benign	0.093	T;T;D;T;D;T;T;D;D;T
Polyphen		0.99	D;.;.;D;.;.;.;.;.;D
Vest4		0.43
MutPred		0.25		Gain of sheet (P = 0.0221);.;.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;.;.;.;Gain of sheet (P = 0.0221);
MVP		0.34
MPC		0.77
ClinPred		0.90	D
GERP RS		3.6
Varity_R		0.075
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-203817318;