chr11-67365449-C-T

Position:

chr11-67365449-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

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:

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]

RAD9A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 link	c.365G>A	p.Arg122His	missense_variant	3/3	ENST00000312438.8	NP_037378.1	Q9UBD9-1
CLCF1	NM_001166212.2 link	c.335G>A	p.Arg112His	missense_variant	3/3		NP_001159684.1	Q9UBD9-2
LOC100130987	NR_024469.1 link	n.424-22086C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCF1	ENST00000312438.8 link	c.365G>A	p.Arg122His	missense_variant	3/3	1	NM_013246.3	ENSP00000309338.7	Q9UBD9-1
ENSG00000256514	ENST00000543494.1 link	c.16+8075G>A		intron_variant		3		ENSP00000480527.1	A0A087WWV3
CLCF1	ENST00000533438.1 link	c.335G>A	p.Arg112His	missense_variant	3/3	2		ENSP00000434122.1	Q9UBD9-2
RAD9A	ENST00000622583.4 link	n.392-22086C>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000458

AC XY:

AN XY:

135492

show subpopulations

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.:

Cov.:

AF XY:

0.000594

AC XY:

432

AN XY:

727024

show subpopulations

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:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74350

show subpopulations

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.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000445

AC:

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

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.0016

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

1.8

L;.

PrimateAI

Benign

0.46

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

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over