chr11-67365422-C-T

Variant names:

• chr11-67365422-C-T
• rs34057094
• NM_013246.3:c.392G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_013246.3(CLCF1):​c.392G>A​(p.Arg131His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,613,428 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (4 hom.)
• Consequence: CLCF1 NM_013246.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.326
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013532847).
• BP6: Variant 11-67365422-C-T is Benign according to our data. Variant chr11-67365422-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1694057.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.392G>A	p.Arg131His	missense	Exon 3 of 3	NP_037378.1	Q9UBD9-1
	CLCF1	NM_001166212.2		c.362G>A	p.Arg121His	missense	Exon 3 of 3	NP_001159684.1	Q9UBD9-2
	LOC100130987	NR_024469.1		n.424-22113C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCF1	ENST00000312438.8	TSL:1 MANE Select	c.392G>A	p.Arg131His	missense	Exon 3 of 3	ENSP00000309338.7	Q9UBD9-1
	ENSG00000256514	ENST00000543494.1	TSL:3	c.16+8102G>A		intron	N/A	ENSP00000480527.1	A0A087WWV3
	CLCF1	ENST00000533438.1	TSL:2	c.362G>A	p.Arg121His	missense	Exon 3 of 3	ENSP00000434122.1	Q9UBD9-2

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 143 AN: 152260 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

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: 0.000838

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000569 AC: 142 AN: 249490 AF XY: 0.000621

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000676

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000911 AC: 1331 AN: 1461168 Hom.: 4 Cov.: 31 AF XY: 0.000900 AC XY: 654 AN XY: 726828

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.00128 AC: 57 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00108 AC: 1196 AN: 1111736

Other (OTH) AF: 0.000928 AC: 56 AN: 60350

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74390

African (AFR) AF: 0.000265 AC: 11 AN: 41474

American (AMR) AF: 0.00477 AC: 73 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000768 Hom.: 0

Bravo AF: 0.000933

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000491

EpiControl AF: 0.000534

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.39	N
PhyloP100		0.33
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.17
Sift	Benign	0.17	T
Sift4G	Benign	0.40	T
Polyphen		0.0020	B
Vest4		0.092
MVP		0.40
MPC		0.43
ClinPred		0.016	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
gMVP		0.22
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs34057094; hg19: chr11-67132893;