rs140997186

Variant names:

• chr11-67365147-GAGCCCCC-G
• rs140997186
• NM_013246.3:c.660_666delGGGGGCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_013246.3(CLCF1):​c.660_666delGGGGGCT​(p.Gly221MetfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.00115 in 1,613,946 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (9 hom.)
• Consequence: CLCF1 NM_013246.3 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.27
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-67365147-GAGCCCCC-G is Benign according to our data. Variant chr11-67365147-GAGCCCCC-G is described in ClinVar as Benign. ClinVar VariationId is 713415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00575 (876/152346) while in subpopulation AFR AF = 0.0199 (828/41580). AF 95% confidence interval is 0.0188. There are 14 homozygotes in GnomAd4. There are 416 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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.660_666delGGGGGCT	p.Gly221MetfsTer6	frameshift	Exon 3 of 3	NP_037378.1	Q9UBD9-1
	CLCF1	NM_001166212.2		c.630_636delGGGGGCT	p.Gly211MetfsTer6	frameshift	Exon 3 of 3	NP_001159684.1	Q9UBD9-2
	LOC100130987	NR_024469.1		n.424-22385_424-22379delCCCCCAG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCF1	ENST00000312438.8	TSL:1 MANE Select	c.660_666delGGGGGCT	p.Gly221MetfsTer6	frameshift	Exon 3 of 3	ENSP00000309338.7	Q9UBD9-1
	ENSG00000256514	ENST00000543494.1	TSL:3	c.16+8370_16+8376delGGGGGCT		intron	N/A	ENSP00000480527.1	A0A087WWV3
	CLCF1	ENST00000533438.1	TSL:2	c.630_636delGGGGGCT	p.Gly211MetfsTer6	frameshift	Exon 3 of 3	ENSP00000434122.1	Q9UBD9-2

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 876 AN: 152228 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00153 AC: 383 AN: 250902 AF XY: 0.00108

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000666 AC: 973 AN: 1461600 Hom.: 9 AF XY: 0.000620 AC XY: 451 AN XY: 727084

African (AFR) AF: 0.0220 AC: 736 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000827 AC: 92 AN: 1112010

Other (OTH) AF: 0.00152 AC: 92 AN: 60390

GnomAD4 genome AF: 0.00575 AC: 876 AN: 152346 Hom.: 14 Cov.: 32 AF XY: 0.00558 AC XY: 416 AN XY: 74496

African (AFR) AF: 0.0199 AC: 828 AN: 41580

American (AMR) AF: 0.00209 AC: 32 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68022

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00295 Hom.: 1

Bravo AF: 0.00679

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=194/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs140997186; hg19: chr11-67132618;