11-67365450-G-C

Position:

chr11-67365450-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013246.3(CLCF1):c.364C>G(p.Arg122Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLCF1
NM_013246.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

Variant links:

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]

CLCF1 links:

ENSG00000256514 (HGNC:):

ENSG00000256514 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.120470375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCF1	NM_013246.3 linkuse as main transcript	c.364C>G	p.Arg122Gly	missense_variant	3/3	ENST00000312438.8	NP_037378.1	Q9UBD9-1
CLCF1	NM_001166212.2 linkuse as main transcript	c.334C>G	p.Arg112Gly	missense_variant	3/3		NP_001159684.1	Q9UBD9-2
LOC100130987	NR_024469.1 linkuse as main transcript	n.424-22085G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCF1	ENST00000312438.8 linkuse as main transcript	c.364C>G	p.Arg122Gly	missense_variant	3/3	1	NM_013246.3	ENSP00000309338.7	Q9UBD9-1
ENSG00000256514	ENST00000543494.1 linkuse as main transcript	c.16+8074C>G		intron_variant		3		ENSP00000480527.1	A0A087WWV3
CLCF1	ENST00000533438.1 linkuse as main transcript	c.334C>G	p.Arg112Gly	missense_variant	3/3	2		ENSP00000434122.1	Q9UBD9-2
RAD9A	ENST00000622583.4 linkuse as main transcript	n.392-22085G>C		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250262

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461526

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.364C>G (p.R122G) alteration is located in exon 3 (coding exon 3) of the CLCF1 gene. This alteration results from a C to G substitution at nucleotide position 364, causing the arginine (R) at amino acid position 122 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.076

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.25

Sift

Benign

0.15

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0

B;.

Vest4

0.078

MutPred

0.51

Loss of MoRF binding (P = 0.038);.;

MVP

0.46

MPC

0.44

ClinPred

0.31

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over