11-67365449-C-T

Position:

• chr11-67365449-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013246.3(CLCF1):​c.365G>A​(p.Arg122His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: CLCF1 NM_013246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05160591).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCF1	NM_013246.3	c.365G>A	p.Arg122His	missense_variant	3/3	ENST00000312438.8	NP_037378.1
CLCF1	NM_001166212.2	c.335G>A	p.Arg112His	missense_variant	3/3		NP_001159684.1
LOC100130987	NR_024469.1	n.424-22086C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCF1	ENST00000312438.8	c.365G>A	p.Arg122His	missense_variant	3/3	1	NM_013246.3	ENSP00000309338.7
ENSG00000256514	ENST00000543494.1	c.16+8075G>A		intron_variant		3		ENSP00000480527.1
CLCF1	ENST00000533438.1	c.335G>A	p.Arg112His	missense_variant	3/3	2		ENSP00000434122.1
RAD9A	ENST00000622583.4	n.392-22086C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000400 AC: 100 AN: 250138 Hom.: 0 AF XY: 0.000458 AC XY: 62 AN XY: 135492

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000771

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000604 AC: 883 AN: 1461496 Hom.: 1 Cov.: 31 AF XY: 0.000594 AC XY: 432 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000745

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74350

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000793 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.00104

EpiControl AF: 0.00101

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0016
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.092	T;T
Polyphen		0.082	B;.
Vest4		0.15
MVP		0.61
MPC		0.89
ClinPred		0.032	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs151050272; hg19: chr11-67132920;