rs765919935

Variant names:

• chr2-202942858-C-T
• rs765919935
• NM_024744.17:c.197C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024744.17. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARF	NM_024744.17	MANE Select	c.197C>T	p.Pro66Leu	missense	Exon 5 of 17	NP_079020.13
	CARF	NM_001104586.4		c.197C>T	p.Pro66Leu	missense	Exon 4 of 16	NP_001098056.1	Q8N187-1
	CARF	NM_001322427.3		c.197C>T	p.Pro66Leu	missense	Exon 5 of 17	NP_001309356.1	Q8N187-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARF	ENST00000438828.4	TSL:1 MANE Select	c.197C>T	p.Pro66Leu	missense	Exon 5 of 17	ENSP00000414644.1	Q8N187-1
	CARF	ENST00000402905.7	TSL:1	c.197C>T	p.Pro66Leu	missense	Exon 4 of 16	ENSP00000384006.2	Q8N187-1
	CARF	ENST00000444724.5	TSL:1	c.197C>T	p.Pro66Leu	missense	Exon 4 of 8	ENSP00000416812.1	F6SXV3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249268 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.8
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.086
Sift	Benign	0.11	T
Sift4G	Benign	0.11	T
Polyphen		0.078	B
Vest4		0.11
MutPred		0.26		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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs765919935; hg19: chr2-203807581;