rs2238647

chr19-18599725-G-Achr19-18599725-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004750.5(CRLF1):c.237C>T(p.Asn79=) 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:2
• Conservation: PhyloP100: -0.500

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 -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 id is 1255324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-18599725-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CRLF1	NM_004750.5	c.237C>T	p.Asn79=	synonymous_variant	2/9	ENST00000392386.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRLF1	ENST00000392386.8	c.237C>T	p.Asn79=	synonymous_variant	2/9	1	NM_004750.5	P1
CRLF1	ENST00000684169.1	c.237C>T	p.Asn79=	synonymous_variant	2/9
CRLF1	ENST00000593286.1	n.489C>T		non_coding_transcript_exon_variant	2/2	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

GnomAD3 exomes AF: 0.247 AC: 56766 AN: 229994 Hom.: 8400 AF XY: 0.239 AC XY: 29870 AN XY: 124946

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 SAS exome AF: 0.222

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

Gnomad4 AFR exome AF: 0.0943

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.516

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.219

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

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.490

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.213

Alfa AF: 0.196 Hom.: 5120

Bravo AF: 0.199

Asia WGS AF: 0.379 AC: 1317 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.37
Dann	Benign	0.86

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: rs2238647; hg19: chr19-18710535; COSMIC: COSV66504340; COSMIC: COSV66504340;