19-18594230-G-A

Position:

• chr19-18594230-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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]

ACMG classification

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 AF: 0.000917 AC: 139 AN: 151592 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00155

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000784 AC: 193 AN: 246164 Hom.: 0 AF XY: 0.000871 AC XY: 117 AN XY: 134376

Gnomad AFR exome AF: 0.000318

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.00156 AC: 2280 AN: 1460600 Hom.: 0 Cov.: 38 AF XY: 0.00153 AC XY: 1114 AN XY: 726596

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.000916 AC: 139 AN: 151698 Hom.: 0 Cov.: 29 AF XY: 0.000863 AC XY: 64 AN XY: 74128

Gnomad4 AFR AF: 0.000242

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.0000948

Gnomad4 NFE AF: 0.00155

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000825 Hom.: 0

Bravo AF: 0.000858

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.3
DANN	Benign	0.89

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

Other links and lift over

dbSNP: rs113715887; hg19: chr19-18705040;