19-18606579-GAGC-GAGCAGC

Variant names:

• chr19-18606579-G-GAGC
• rs34503316
• NM_004750.5:c.75_77dupGCT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004750.5(CRLF1):​c.75_77dupGCT​(p.Leu26dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 992,356 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: CRLF1 NM_004750.5 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• cold-induced sweating syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004750.5. 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
	CRLF1	NM_004750.5	MANE Select	c.75_77dupGCT	p.Leu26dup	disruptive_inframe_insertion	Exon 1 of 9	NP_004741.1	O75462

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRLF1	ENST00000392386.8	TSL:1 MANE Select	c.75_77dupGCT	p.Leu26dup	disruptive_inframe_insertion	Exon 1 of 9	ENSP00000376188.2	O75462
	CRLF1	ENST00000928241.1		c.75_77dupGCT	p.Leu26dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000598300.1
	CRLF1	ENST00000971859.1		c.75_77dupGCT	p.Leu26dup	disruptive_inframe_insertion	Exon 1 of 10	ENSP00000641918.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000705 AC: 7 AN: 992356 Hom.: 0 Cov.: 0 AF XY: 0.0000129 AC XY: 6 AN XY: 466884

African (AFR) AF: 0.00 AC: 0 AN: 19976

American (AMR) AF: 0.00 AC: 0 AN: 5100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11030

East Asian (EAS) AF: 0.00 AC: 0 AN: 18430

South Asian (SAS) AF: 0.000214 AC: 4 AN: 18694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2498

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 864780

Other (OTH) AF: 0.0000803 AC: 3 AN: 37366

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 192

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34503316; hg19: chr19-18717389;