chr19-18594230-G-A
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1
The NM_004750.5(CRLF1):c.1212+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,612,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00092 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0016 ( 0 hom. )
Consequence
CRLF1
NM_004750.5 intron
NM_004750.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0360
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 19-18594230-G-A is Benign according to our data. Variant chr19-18594230-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1971476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000916 (139/151698) while in subpopulation NFE AF= 0.00155 (105/67834). AF 95% confidence interval is 0.00131. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CRLF1 | NM_004750.5 | c.1212+17C>T | intron_variant | ENST00000392386.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CRLF1 | ENST00000392386.8 | c.1212+17C>T | intron_variant | 1 | NM_004750.5 | P1 | |||
| CRLF1 | ENST00000684169.1 | c.1212+17C>T | intron_variant | ||||||
| CRLF1 | ENST00000594325.1 | n.189+17C>T | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes 0.000917 AC: 139AN: 151592Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.000784 AC: 193AN: 246164Hom.: 0 AF XY: 0.000871 AC XY: 117AN XY: 134376
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GnomAD4 exome AF: 0.00156 AC: 2280AN: 1460600Hom.: 0 Cov.: 38 AF XY: 0.00153 AC XY: 1114AN XY: 726596
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GnomAD4 genome 0.000916 AC: 139AN: 151698Hom.: 0 Cov.: 29 AF XY: 0.000863 AC XY: 64AN XY: 74128
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2023 | Variant summary: CRLF1 c.1212+17C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00078 in 246164 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in CRLF1 causing Cold-Induced Sweating Syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.1212+17C>T in individuals affected with Cold-Induced Sweating Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at