19-18604393-C-A

Variant names:

• chr19-18604393-C-A
• rs7249956
• NM_004750.5:c.115+2149G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004750.5(CRLF1):​c.115+2149G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,196 control chromosomes in the GnomAD database, including 3,995 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (3995 hom., cov: 33)
• Consequence: CRLF1 NM_004750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Cold-induced sweating syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cold-induced sweating syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.115+2149G>T		intron_variant	Intron 1 of 8	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.115+2149G>T		intron_variant	Intron 1 of 8	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.115+2149G>T		intron_variant	Intron 1 of 8			ENSP00000506849.1
CRLF1	ENST00000593286.1	n.367+2982G>T		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33095 AN: 152078 Hom.: 3971 Cov.: 33

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.484

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.218 AC: 33161 AN: 152196 Hom.: 3995 Cov.: 33 AF XY: 0.221 AC XY: 16462 AN XY: 74418

African (AFR) AF: 0.177 AC: 7347 AN: 41530

American (AMR) AF: 0.311 AC: 4758 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 425 AN: 3472

East Asian (EAS) AF: 0.484 AC: 2496 AN: 5160

South Asian (SAS) AF: 0.224 AC: 1081 AN: 4824

European-Finnish (FIN) AF: 0.228 AC: 2423 AN: 10604

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13855 AN: 67994

Other (OTH) AF: 0.233 AC: 492 AN: 2110

Alfa AF: 0.204 Hom.: 1773

Bravo AF: 0.226

Asia WGS AF: 0.386 AC: 1337 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.7
DANN	Benign	0.45
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs7249956; hg19: chr19-18715203;