chr17-42695534-CTT-C

Variant names:

• chr17-42695534-CTT-C
• rs786204799
• NM_003632.3:c.3008_3009delTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003632.3(CNTNAP1):​c.3008_3009delTT​(p.Phe1003fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000689 in 1,452,054 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CNTNAP1 NM_003632.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49
• Publications: 0 publications found

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

ENSG00000267765 (HGNC:58591):

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP1	NM_003632.3	c.3008_3009delTT	p.Phe1003fs	frameshift_variant	Exon 19 of 24	ENST00000264638.9	NP_003623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP1	ENST00000264638.9	c.3008_3009delTT	p.Phe1003fs	frameshift_variant	Exon 19 of 24	1	NM_003632.3	ENSP00000264638.3
CNTNAP1	ENST00000591662.1	n.*769_*770delTT		non_coding_transcript_exon_variant	Exon 19 of 24	1		ENSP00000466571.1
CNTNAP1	ENST00000591662.1	n.*769_*770delTT		3_prime_UTR_variant	Exon 19 of 24	1		ENSP00000466571.1
ENSG00000267765	ENST00000592440.1	n.363+3568_363+3569delAA		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452054 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 720254

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39386

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104300

Other (OTH) AF: 0.00 AC: 0 AN: 59896

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5

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

Other links and lift over

dbSNP: rs786204799; hg19: chr17-40847552;