rs751050956

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003632.3(CNTNAP1):c.2901_2902delCT(p.Cys968PhefsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CNTNAP1
NM_003632.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.97

Publications

3 publications found

Variant links:

Genes affected

CNTNAP1 (HGNC:8011): (contactin associated protein 1) The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for 'contactin-associated protein,' includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. [provided by RefSeq, Jan 2009]

CNTNAP1 Gene-Disease associations (from GenCC):

lethal congenital contracture syndrome 7
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
hypomyelination neuropathy-arthrogryposis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CNTNAP1 links:

ENSG00000267765 (HGNC:58591):

ENSG00000267765 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-42693444-CCT-C is Pathogenic according to our data. Variant chr17-42693444-CCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 204313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003632.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP1	NM_003632.3	MANE Select	c.2901_2902delCT	p.Cys968PhefsTer11	frameshift	Exon 18 of 24	NP_003623.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNTNAP1	ENST00000264638.9	TSL:1 MANE Select	c.2901_2902delCT	p.Cys968PhefsTer11	frameshift	Exon 18 of 24	ENSP00000264638.3
CNTNAP1	ENST00000591662.1	TSL:1	n.662_663delCT		non_coding_transcript_exon	Exon 18 of 24	ENSP00000466571.1
CNTNAP1	ENST00000591662.1	TSL:1	n.662_663delCT		3_prime_UTR	Exon 18 of 24	ENSP00000466571.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251486

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461894

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1112012

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68054

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000712

Hom.:

Bravo

AF:

0.0000378

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jun 22, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31397905, 28374019, 24319099, 34930662, 33820833, 31618753)

Nov 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Cys968Phefs*11) in the CNTNAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNTNAP1 are known to be pathogenic (PMID: 24319099). This variant is present in population databases (rs751050956, ExAC 0.004%). This variant has been observed in individual(s) with CNTNAP1-related conditions (PMID: 24319099, 31397905). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204313).

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lethal congenital contracture syndrome 7

Pathogenic:3

May 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 30, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes:PVS1; PM2; PM3; PP1S

Mar 30, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This frameshifting variant is predicted to result in a premature stop codon and is therefore considered a loss-of-function mutation. This variant has been previously reported as a homozygous change in three siblings with arthrogryposis, hypotonia, respiratory distress, and feeding difficulties (PMID: 24319099). It is present as a heterozygous change in the gnomAD population database at a frequency of 0.003% (7/277236). Based on the available evidence, the c.2901_2902delCT (p.Cys968PhefsTer11) variant is classified as a pathogenic change.

Neuropathy, congenital hypomyelinating, 3

Pathogenic:3

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 13, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CNTNAP1 c.2901_2902delCT (p.Cys968PhefsX11) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2e-05 in 251486 control chromosomes (gnomAD). c.2901_2902delCT has been reported in the literature in an individual(s) affected with Neuropathy, Congenital Hypomyelinating, 3 who was compound heterozygous with a pathogenic gross deletion variant (Bowling_2022). The following publication has been ascertained in the context of this evaluation (PMID: 34930662). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2901_2902del;p.(Cys968Phefs*11) is a null frameshift variant (NMD) in the CNTNAP1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 204313; OMIM: 602346.0003; PMID: 24319099) - PS4_moderate. This variant is not present in population databases (rs751050956, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Cys968Phefs*11) was detected in trans with a pathogenic variant (PMID: 24319099) - PM3.The variant co-segregated with disease in multiple affected family members (PMID: 24319099) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over