11-67365147-GAGCCCCC-G

Position:

• chr11-67365147-GAGCCCCC-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BS1 BS2

The NM_013246.3(CLCF1):​c.660_666del​(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

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]

LOC100130987 (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

Verdict is Benign. Variant got -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0265 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 11-67365147-GAGCCCCC-G is Benign according to our data. Variant chr11-67365147-GAGCCCCC-G is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCF1	NM_013246.3	c.660_666del	p.Gly221MetfsTer6	frameshift_variant	3/3	ENST00000312438.8	NP_037378.1
LOC100130987	NR_024469.1	n.424-22385_424-22379del		intron_variant, non_coding_transcript_variant
CLCF1	NM_001166212.2	c.630_636del	p.Gly211MetfsTer6	frameshift_variant	3/3		NP_001159684.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCF1	ENST00000312438.8	c.660_666del	p.Gly221MetfsTer6	frameshift_variant	3/3	1	NM_013246.3	ENSP00000309338	P1
CLCF1	ENST00000533438.1	c.630_636del	p.Gly211MetfsTer6	frameshift_variant	3/3	2		ENSP00000434122
RAD9A	ENST00000622583.4	n.392-22385_392-22379del		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.00153 AC: 383 AN: 250902 Hom.: 7 AF XY: 0.00108 AC XY: 147 AN XY: 135762

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 SAS exome AF: 0.0000980

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

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000827

Gnomad4 OTH exome AF: 0.00152

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

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00295 Hom.: 1

Bravo AF: 0.00679

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 20, 2022

Variant summary: CLCF1 c.660_666delGGGGGCT (p.Gly221MetfsX6) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.0015 in 250902 control chromosomes, predominantly at a frequency of 0.021 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 84 fold of the estimated maximal expected allele frequency for a pathogenic variant in CLCF1 causing Cold-Induced Sweating Syndrome phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.660_666delGGGGGCT in individuals affected with Cold-Induced Sweating Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs140997186; hg19: chr11-67132618;