11-58624065-A-G

Variant names:

• chr11-58624065-A-G
• rs17152779
• NM_000614.4:c.146A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000614.4(CNTF):​c.146A>G​(p.Asn49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,612,108 control chromosomes in the GnomAD database, including 437 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (232 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (205 hom.)
• Consequence: CNTF NM_000614.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.666

Genes affected

CNTF (HGNC:2169): (ciliary neurotrophic factor) The protein encoded by this gene is a polypeptide hormone whose actions appear to be restricted to the nervous system where it promotes neurotransmitter synthesis and neurite outgrowth in certain neuronal populations. The protein is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. A read-through transcript variant composed of the upstream ZFP91 gene and CNTF sequence has been identified, but it is thought to be non-coding. Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Oct 2010]

ZFP91-CNTF (HGNC:33441): (ZFP91-CNTF readthrough (NMD candidate)) This gene represents a read-through transcript composed of ZFP91 and CNTF sequence. This transcript is thought to be non-coding because it would be subject to nonsense-mediated mRNA decay (NMD). Read-through transcription of ZFP91 and CNTF has also been observed in mouse. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015153289).
• BP6: Variant 11-58624065-A-G is Benign according to our data. Variant chr11-58624065-A-G is described in ClinVar as [Benign]. Clinvar id is 768450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTF	NM_000614.4	c.146A>G	p.Asn49Ser	missense_variant	Exon 2 of 2	ENST00000361987.6	NP_000605.1
ZFP91-CNTF	NR_024091.1	n.1876A>G		non_coding_transcript_exon_variant	Exon 13 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTF	ENST00000361987.6	c.146A>G	p.Asn49Ser	missense_variant	Exon 2 of 2	1	NM_000614.4	ENSP00000355370.4
ZFP91-CNTF	ENST00000389919.8	n.*118A>G		non_coding_transcript_exon_variant	Exon 13 of 13	2		ENSP00000455911.1
ZFP91-CNTF	ENST00000389919.8	n.*118A>G		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000455911.1

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4570 AN: 152040 Hom.: 233 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.00796 AC: 1960 AN: 246386 Hom.: 93 AF XY: 0.00593 AC XY: 790 AN XY: 133280

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000996

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00324 AC: 4723 AN: 1459950 Hom.: 205 Cov.: 32 AF XY: 0.00285 AC XY: 2068 AN XY: 726206

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00623

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000296

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.0301 AC: 4575 AN: 152158 Hom.: 232 Cov.: 32 AF XY: 0.0282 AC XY: 2100 AN XY: 74410

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00569 Hom.: 62

Bravo AF: 0.0347

ESP6500AA AF: 0.102 AC: 450

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00946 AC: 1149

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.5
DANN	Benign	0.72
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.077
Sift	Benign	0.74	T
Sift4G	Benign	0.54	T
Polyphen		0.012	B
Vest4		0.019
MVP		0.46
MPC		0.022
ClinPred		0.0034	T
GERP RS		3.5
Varity_R		0.039
gMVP		0.066

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: rs17152779; hg19: chr11-58391538;