19-18593718-C-T

Variant names:

• chr19-18593718-C-T
• rs7256319
• NM_004750.5:c.1256-139G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004750.5(CRLF1):​c.1256-139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,520,116 control chromosomes in the GnomAD database, including 263,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29927 hom., cov: 33)
  • Exomes 𝑓: 0.58 (233851 hom.)
• Consequence: CRLF1 NM_004750.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0490
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-18593718-C-T is Benign according to our data. Variant chr19-18593718-C-T is described in ClinVar as Benign. ClinVar VariationId is 1270588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.707 is higher than 0.05.

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.1256-139G>A		intron	N/A	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.1256-139G>A		intron	N/A	ENSP00000376188.2	O75462
	CRLF1	ENST00000928241.1		c.1337-139G>A		intron	N/A	ENSP00000598300.1
	CRLF1	ENST00000971859.1		c.1322-139G>A		intron	N/A	ENSP00000641918.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94675 AN: 152012 Hom.: 29898 Cov.: 33

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.584

GnomAD4 exome AF: 0.583 AC: 797161 AN: 1367986 Hom.: 233851 AF XY: 0.579 AC XY: 388757 AN XY: 671720

African (AFR) AF: 0.716 AC: 22262 AN: 31078

American (AMR) AF: 0.585 AC: 20061 AN: 34286

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 12402 AN: 24140

East Asian (EAS) AF: 0.614 AC: 21689 AN: 35324

South Asian (SAS) AF: 0.475 AC: 36717 AN: 77280

European-Finnish (FIN) AF: 0.676 AC: 27842 AN: 41196

Middle Eastern (MID) AF: 0.501 AC: 2693 AN: 5380

European-Non Finnish (NFE) AF: 0.584 AC: 620687 AN: 1062506

Other (OTH) AF: 0.578 AC: 32808 AN: 56796

GnomAD4 genome AF: 0.623 AC: 94754 AN: 152130 Hom.: 29927 Cov.: 33 AF XY: 0.621 AC XY: 46191 AN XY: 74356

African (AFR) AF: 0.714 AC: 29653 AN: 41522

American (AMR) AF: 0.568 AC: 8683 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1712 AN: 3468

East Asian (EAS) AF: 0.598 AC: 3082 AN: 5156

South Asian (SAS) AF: 0.476 AC: 2294 AN: 4824

European-Finnish (FIN) AF: 0.672 AC: 7114 AN: 10584

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40277 AN: 67982

Other (OTH) AF: 0.588 AC: 1242 AN: 2114

Alfa AF: 0.609 Hom.: 6146

Bravo AF: 0.620

Asia WGS AF: 0.582 AC: 2021 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.5
DANN	Benign	0.86
PhyloP100		-0.049
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7256319; hg19: chr19-18704528;