Variant 19-18597033-C-CG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004750.5(CRLF1):c.713_714insC(p.Pro239AlafsTer91) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,612,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

CRLF1
NM_004750.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 8.88

Variant links:

Genes affected

CRLF1 (HGNC:2364): (cytokine receptor like factor 1) This gene encodes a member of the cytokine type I receptor family. The protein forms a secreted complex with cardiotrophin-like cytokine factor 1 and acts on cells expressing ciliary neurotrophic factor receptors. The complex can promote survival of neuronal cells. Mutations in this gene result in Crisponi syndrome and cold-induced sweating syndrome. [provided by RefSeq, Oct 2009]

CRLF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-18597033-C-CG is Pathogenic according to our data. Variant chr19-18597033-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 216913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRLF1	NM_004750.5 linkuse as main transcript	c.713_714insC	p.Pro239AlafsTer91	frameshift_variant	5/9	ENST00000392386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CRLF1	ENST00000392386.8 linkuse as main transcript	c.713_714insC	p.Pro239AlafsTer91	frameshift_variant	5/9	1	NM_004750.5	P1
CRLF1	ENST00000597131.1 linkuse as main transcript	c.178_179insC	p.Pro61AlafsTer?	frameshift_variant	2/4	2
CRLF1	ENST00000684169.1 linkuse as main transcript	c.713_714insC	p.Pro239AlafsTer91	frameshift_variant	5/9

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000899

AC:

AN:

244670

Hom.:

AF XY:

0.0000749

AC XY:

AN XY:

133598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000437

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000457

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460328

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000381

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Bravo

AF:

0.000102

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cold-induced sweating syndrome 1

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Feb 11, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in the Roma population (Spain) -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.713dupC (p.P239Afs*91) alteration, located in exon 5 (coding exon 5) of the CRLF1 gene, consists of a duplication of C at position 713, causing a translational frameshift with a predicted alternate stop codon after 91 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.713dupC allele has an overall frequency of 0.01% (26/275984) total alleles studied. The highest observed frequency was 0.05% (17/35212) of Latino alleles. This variant has been reported in the homozygous and compound heterozygous states in individuals with CRLF1-related cold-induced sweating syndrome (Dagoneau, 2007; Aljabari, 2013; González Fernández, 2013; Piras, 2014). Based on the available evidence, this alteration is classified as pathogenic. -

CRLF1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

The CRLF1 c.713dupC variant is predicted to result in a frameshift and premature protein termination (p.Pro239Alafs*91). This variant was reported in the homozygous state in a family with Crisponi syndrome (Family 3 in Dagoneau et al. 2007. PubMed ID: 17436251), in the homozygous state in patients with cold-induced sweating syndrome (González Fernández et al. 2013. PubMed ID: 24008591; Herholz et al. 2011. PubMed ID: 21326283), and in the compound heterozygous state in a family with achalasia (Busch et al. 2017. PubMed ID: 27976805). Functional analysis showed that this variant disrupts CRLF1 secretion (Herholz et. 2011. PubMed ID: 21326283). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in CRLF1 are expected to be pathogenic. Based on this evidence, this variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 216913). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive cold-induced sweating syndrome (PMID: 17436251, 24488861, 27976805). This variant is present in population databases (rs768727082, gnomAD 0.05%). This sequence change creates a premature translational stop signal (p.Pro239Alafs*91) in the CRLF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CRLF1 are known to be pathogenic (PMID: 17436252, 19012339). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over