9-34564630-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_147164.3(CNTFR):c.288C>A(p.His96Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,612,682 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: CNTFR NM_147164.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058802336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTFR	NM_147164.3	c.288C>A	p.His96Gln	missense_variant	4/10	ENST00000378980.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTFR	ENST00000378980.8	c.288C>A	p.His96Gln	missense_variant	4/10	1	NM_147164.3	P1
CNTFR	ENST00000351266.8	c.288C>A	p.His96Gln	missense_variant	3/9	1		P1
CNTFR	ENST00000610543.4	c.288C>A	p.His96Gln	missense_variant	4/10	5		P1
CNTFR	ENST00000417345.2	c.288C>A	p.His96Gln	missense_variant	4/7	3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000239 AC: 59 AN: 246494 Hom.: 0 AF XY: 0.000210 AC XY: 28 AN XY: 133408

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000518 AC: 757 AN: 1460556 Hom.: 1 Cov.: 32 AF XY: 0.000464 AC XY: 337 AN XY: 726392

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000494

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000626

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74306

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000431

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000206 AC: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.288C>A (p.H96Q) alteration is located in exon 4 (coding exon 2) of the CNTFR gene. This alteration results from a C to A substitution at nucleotide position 288, causing the histidine (H) at amino acid position 96 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.84
DEOGEN2	Benign	0.27	T;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N;N;N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N;N;.;N
REVEL	Benign	0.15
Sift	Benign	0.60	T;T;.;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.0060	B;B;B;.
Vest4		0.55
MutPred		0.40		Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);
MVP		0.51
MPC		0.40
ClinPred		0.016	T
GERP RS		2.4
Varity_R		0.095
gMVP		0.73

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: rs145830233; hg19: chr9-34564628; COSMIC: COSV100667425; COSMIC: COSV100667425;