rs193920748

Positions:

• chr9-34556323-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000378980.8(CNTFR):​c.700G>C​(p.Asp234His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CNTFR ENST00000378980.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.52

Genes affected

CNTFR (HGNC:2170): (ciliary neurotrophic factor receptor) This gene encodes a member of the type 1 cytokine receptor family. The encoded protein is the ligand-specific component of a tripartite receptor for ciliary neurotrophic factor, which plays a critical role in neuronal cell survival, differentiation and gene expression. Binding of ciliary neurotrophic factor to the encoded protein recruits the transmembrane components of the receptor, gp130 and leukemia inhibitory factor receptor, facilitating signal transduction. Single nucleotide polymorphisms in this gene may be associated with variations in muscle strength, as well as early onset of eating disorders. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTFR	NM_147164.3	c.700G>C	p.Asp234His	missense_variant	7/10	ENST00000378980.8	NP_671693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTFR	ENST00000378980.8	c.700G>C	p.Asp234His	missense_variant	7/10	1	NM_147164.3	ENSP00000368265	P1
CNTFR	ENST00000351266.8	c.700G>C	p.Asp234His	missense_variant	6/9	1		ENSP00000242338	P1
CNTFR	ENST00000610543.4	c.700G>C	p.Asp234His	missense_variant	7/10	5		ENSP00000480451	P1
CNTFR	ENST00000417345.2	c.700G>C	p.Asp234His	missense_variant	7/7	3		ENSP00000388082

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.6	L;L;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.3	D;D;.;D
REVEL	Uncertain	0.41
Sift	Benign	0.12	T;T;.;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.61
MutPred		0.38		Gain of catalytic residue at D234 (P = 0.1258);Gain of catalytic residue at D234 (P = 0.1258);Gain of catalytic residue at D234 (P = 0.1258);Gain of catalytic residue at D234 (P = 0.1258);
MVP		0.91
MPC		1.2
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.60

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: rs193920748; hg19: chr9-34556321; COSMIC: COSV63635184;