rs1555642784

Positions:

• chr17-42688979-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003632.3(CNTNAP1):​c.1561dup​(p.Leu521ProfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP1 NM_003632.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.73

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 17-42688979-T-TC is Pathogenic according to our data. Variant chr17-42688979-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 254173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP1	NM_003632.3	c.1561dup	p.Leu521ProfsTer12	frameshift_variant	10/24	ENST00000264638.9	NP_003623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP1	ENST00000264638.9	c.1561dup	p.Leu521ProfsTer12	frameshift_variant	10/24	1	NM_003632.3	ENSP00000264638	P1
CNTNAP1	ENST00000591662.1	c.1561dup	p.Leu521ProfsTer12	frameshift_variant, NMD_transcript_variant	10/24	1		ENSP00000466571
	ENST00000592440.1	n.364-5438_364-5437insG		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 01, 2022	PP1, PM2, PM3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2018	The c.1561dupC variant in the CNTNAP1 gene has been reported previously in the homozygous state in three siblings with arthrogryposis multiplex congenita from a consanguineous Arab family (Lakhani et al., 2017). The c.1561dupC variant causes a frameshift starting with codon Leucine 521, changes this amino acid to a Proline residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Leu521ProfsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1561dupC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1561dupC as a pathogenic variant. -

Lethal congenital contracture syndrome 7 Pathogenic:2

Pathogenic, no assertion criteria provided	research	Christopher A. Walsh Laboratory, Boston Children's Hospital	Aug 24, 2016	This CNTNAP1 frameshift mutation was found in homozygosity in siblings affected with arthrogryposis multiplex congenita, consistent with the previously reported phenotype associated with CNTNAP1 frameshift mutations. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555642784; hg19: chr17-40840997;