NM_013246.3:c.163C>A

Variant names:

• chr11-67367480-G-T
• rs560558450
• NM_013246.3:c.163C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013246.3(CLCF1):​c.163C>A​(p.Arg55Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCF1 NM_013246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18573794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCF1	NM_013246.3	c.163C>A	p.Arg55Ser	missense_variant	Exon 2 of 3	ENST00000312438.8	NP_037378.1
CLCF1	NM_001166212.2	c.133C>A	p.Arg45Ser	missense_variant	Exon 2 of 3		NP_001159684.1
LOC100130987	NR_024469.1	n.424-20055G>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCF1	ENST00000312438.8	c.163C>A	p.Arg55Ser	missense_variant	Exon 2 of 3	1	NM_013246.3	ENSP00000309338.7
ENSG00000256514	ENST00000543494.1	c.16+6044C>A		intron_variant	Intron 1 of 3	3		ENSP00000480527.1
CLCF1	ENST00000533438.1	c.133C>A	p.Arg45Ser	missense_variant	Exon 2 of 3	2		ENSP00000434122.1
RAD9A	ENST00000622583.4	n.392-20055G>T		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.00026
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.060	N;.
PhyloP100		4.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.23
Sift	Benign	0.80	T;T
Sift4G	Uncertain	0.018	D;D
Vest4		0.55
ClinPred		0.66	D
GERP RS		4.5
Varity_R		0.23
gMVP		0.39
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs560558450; hg19: chr11-67134951;