Genetic Variant CNTFR:p.Val354Ile (chr9-34552219-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_147164.3(CNTFR):c.1060G>A(p.Val354Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,575,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CNTFR
NM_147164.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

Publications

0 publications found

Variant links:

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]

CNTFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10705945).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147164.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNTFR	NM_147164.3	MANE Select	c.1060G>A	p.Val354Ile	missense	Exon 9 of 10	NP_671693.1	P26992
CNTFR	NM_001207011.2		c.1060G>A	p.Val354Ile	missense	Exon 9 of 10	NP_001193940.1	P26992
CNTFR	NM_001842.5		c.1060G>A	p.Val354Ile	missense	Exon 8 of 9	NP_001833.1	P26992

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNTFR	ENST00000378980.8	TSL:1 MANE Select	c.1060G>A	p.Val354Ile	missense	Exon 9 of 10	ENSP00000368265.3	P26992
CNTFR	ENST00000351266.8	TSL:1	c.1060G>A	p.Val354Ile	missense	Exon 8 of 9	ENSP00000242338.4	P26992
CNTFR	ENST00000868706.1		c.1114G>A	p.Val372Ile	missense	Exon 9 of 10	ENSP00000538765.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000218

AC:

AN:

178740

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.0000960

Gnomad AMR exome

AF:

0.000806

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000148

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000138

AC:

197

AN:

1423022

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

101

AN XY:

704288

show subpopulations

African (AFR)

AF:

0.000214

AC:

AN:

32742

American (AMR)

AF:

0.000819

AC:

AN:

39088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25444

East Asian (EAS)

AF:

0.00

AC:

AN:

37754

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49300

Middle Eastern (MID)

AF:

0.00215

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.000114

AC:

125

AN:

1092770

Other (OTH)

AF:

0.000339

AC:

AN:

58918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41552

American (AMR)

AF:

0.000588

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67984

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000103

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000160

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.16

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.58

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.90

PhyloP100

1.4

PrimateAI

Benign

0.47

PROVEAN

Benign

0.0

REVEL

Benign

0.097

Sift

Benign

0.32

Sift4G

Benign

0.34

Polyphen

0.91

Vest4

0.20

MVP

0.43

MPC

0.32

ClinPred

0.031

GERP RS

4.5

Varity_R

0.043

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over