rs2238647

Variant names:

• chr19-18599725-G-A
• rs2238647
• NM_004750.5:c.237C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-18599725-G-A
• chr19-18599725-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004750.5(CRLF1):​c.237C>T​(p.Asn79Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,605,194 control chromosomes in the GnomAD database, including 41,415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3475 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37940 hom.)
• Consequence: CRLF1 NM_004750.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.500
• Publications: 28 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 19-18599725-G-A is Benign according to our data. Variant chr19-18599725-G-A is described in ClinVar as Benign. ClinVar VariationId is 1255324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRLF1	NM_004750.5	c.237C>T	p.Asn79Asn	synonymous_variant	Exon 2 of 9	ENST00000392386.8	NP_004741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRLF1	ENST00000392386.8	c.237C>T	p.Asn79Asn	synonymous_variant	Exon 2 of 9	1	NM_004750.5	ENSP00000376188.2
CRLF1	ENST00000684169.1	c.237C>T	p.Asn79Asn	synonymous_variant	Exon 2 of 9			ENSP00000506849.1
CRLF1	ENST00000593286.1	n.489C>T		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29588 AN: 152052 Hom.: 3458 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.247 AC: 56766 AN: 229994 AF XY: 0.239

Gnomad AFR exome AF: 0.0984

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.0993

Gnomad EAS exome AF: 0.498

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.218 AC: 316306 AN: 1453024 Hom.: 37940 Cov.: 34 AF XY: 0.216 AC XY: 156155 AN XY: 722078

African (AFR) AF: 0.0943 AC: 3153 AN: 33424

American (AMR) AF: 0.391 AC: 16742 AN: 42788

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2777 AN: 25890

East Asian (EAS) AF: 0.516 AC: 20327 AN: 39412

South Asian (SAS) AF: 0.218 AC: 18573 AN: 85222

European-Finnish (FIN) AF: 0.230 AC: 12035 AN: 52342

Middle Eastern (MID) AF: 0.142 AC: 815 AN: 5740

European-Non Finnish (NFE) AF: 0.206 AC: 228759 AN: 1108198

Other (OTH) AF: 0.219 AC: 13125 AN: 60008

GnomAD4 genome AF: 0.195 AC: 29623 AN: 152170 Hom.: 3475 Cov.: 32 AF XY: 0.199 AC XY: 14811 AN XY: 74390

African (AFR) AF: 0.101 AC: 4212 AN: 41540

American (AMR) AF: 0.294 AC: 4500 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 369 AN: 3468

East Asian (EAS) AF: 0.490 AC: 2528 AN: 5162

South Asian (SAS) AF: 0.225 AC: 1084 AN: 4814

European-Finnish (FIN) AF: 0.228 AC: 2419 AN: 10596

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13784 AN: 67992

Other (OTH) AF: 0.213 AC: 449 AN: 2112

Alfa AF: 0.197 Hom.: 6823

Bravo AF: 0.199

Asia WGS AF: 0.379 AC: 1317 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.37
DANN	Benign	0.86
PhyloP100		-0.50
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: rs2238647; hg19: chr19-18710535; COSMIC: COSV66504340; COSMIC: COSV66504340;