11-67367595-GCA-TCG

Variant names:

• chr11-67367595-GCA-TCG
• NM_013246.3:c.46_48delTGCinsCGA
• CLCF1 p.Cys16Arg

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_013246.3(CLCF1):​c.46_48delTGCinsCGA​(p.Cys16Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCF1 NM_013246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• Publications: 0 publications found

Genes affected

CLCF1 (HGNC:17412): (cardiotrophin like cytokine factor 1) This gene is a member of the glycoprotein (gp)130 cytokine family and encodes cardiotrophin-like cytokine factor 1 (CLCF1). CLCF1 forms a heterodimer complex with cytokine receptor-like factor 1 (CRLF1). This dimer competes with ciliary neurotrophic factor (CNTF) for binding to the ciliary neurotrophic factor receptor (CNTFR) complex, and activates the Jak-STAT signaling cascade. CLCF1 can be actively secreted from cells by forming a complex with soluble type I CRLF1 or soluble CNTFR. CLCF1 is a potent neurotrophic factor, B-cell stimulatory agent and neuroendocrine modulator of pituitary corticotroph function. Defects in CLCF1 cause cold-induced sweating syndrome 2 (CISS2). This syndrome is characterized by a profuse sweating after exposure to cold as well as congenital physical abnormalities of the head and spine. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

ENSG00000256514 (HGNC:):

RAD9A (HGNC:9827): (RAD9 checkpoint clamp component A) This gene product is highly similar to Schizosaccharomyces pombe rad9, a cell cycle checkpoint protein required for cell cycle arrest and DNA damage repair. This protein possesses 3' to 5' exonuclease activity, which may contribute to its role in sensing and repairing DNA damage. It forms a checkpoint protein complex with RAD1 and HUS1. This complex is recruited by checkpoint protein RAD17 to the sites of DNA damage, which is thought to be important for triggering the checkpoint-signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_013246.3 (CLCF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013246.3. 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
	CLCF1	NM_013246.3	MANE Select	c.46_48delTGCinsCGA	p.Cys16Arg	missense	N/A	NP_037378.1	Q9UBD9-1
	CLCF1	NM_001166212.2		c.16_18delTGCinsCGA	p.Cys6Arg	missense	N/A	NP_001159684.1	Q9UBD9-2
	LOC100130987	NR_024469.1		n.424-19940_424-19938delGCAinsTCG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCF1	ENST00000312438.8	TSL:1 MANE Select	c.46_48delTGCinsCGA	p.Cys16Arg	missense	N/A	ENSP00000309338.7	Q9UBD9-1
	ENSG00000256514	ENST00000543494.1	TSL:3	c.16+5927_16+5929delTGCinsCGA		intron	N/A	ENSP00000480527.1	A0A087WWV3
	CLCF1	ENST00000533438.1	TSL:2	c.16_18delTGCinsCGA	p.Cys6Arg	missense	N/A	ENSP00000434122.1	Q9UBD9-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-67135066;