rs779027563

chr17-42687838-G-Cchr17-42687838-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_003632.3(CNTNAP1):c.1163G>C(p.Arg388Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNTNAP1 NM_003632.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.33

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CNTNAP1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 17-42687838-G-C is Pathogenic according to our data. Variant chr17-42687838-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522842.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP1	NM_003632.3	c.1163G>C	p.Arg388Pro	missense_variant	8/24	ENST00000264638.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP1	ENST00000264638.9	c.1163G>C	p.Arg388Pro	missense_variant	8/24	1	NM_003632.3	P1
CNTNAP1	ENST00000591662.1	c.1163G>C	p.Arg388Pro	missense_variant, NMD_transcript_variant	8/24	1
	ENST00000592440.1	n.364-4296C>G		intron_variant, non_coding_transcript_variant		2
CNTNAP1	ENST00000586801.1	n.578G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lethal congenital contracture syndrome 7 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Mar 26, 2017	A recent study reported this c.1163G>C (p.R388P) variant in homozygous status in a patient with similar features including hypotonia, minimal gag reflex and abnormalities within cerebral white matter revealed by brain MRI (PMID: 27668699). -
Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 15, 2018	The homozygous p.Arg388Pro variant was identified by our study in one individual with lethal congenital contracture syndrome. This variant has been identified in the literature in the homozygous state in one Guatamalan proband showing symptoms of neonatal onset of respiratory failure requiring tracheostomy, bilateral hearing loss with submucosal left cleft palate, and seizures. This proband also had a deceased older brother who died in the neonatal period of respiratory failure. The brother's genotype was not stated (Vanderver et al. 2016, PMID: 27159321). This variant has been identified in <0.01% (1/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs779027563). The Arginine (Arg) at position 299 is conserved in mammals but not evolutionarily distant species, slightly raising the possibility that a change at this position may not be tolerated. Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2022

The c.1163G>C (p.R388P) alteration is located in exon 8 (coding exon 8) of the CNTNAP1 gene. This alteration results from a G to C substitution at nucleotide position 1163, causing the arginine (R) at amino acid position 388 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/251460) total alleles studied. The highest observed frequency was 0.003% (1/30616) of South Asian alleles. This alteration was detected in the homozygous state in multiple individuals with CNTNAP1-related congenital hypomyelinating neuropathy (Mehta, 2016; Conant, 2018; Wojcik, 2019). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Neuropathy, congenital hypomyelinating, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.87	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		0.68	P
Vest4		0.91
MutPred		0.71		Loss of MoRF binding (P = 0.0084);
MVP		0.81
MPC		2.2
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.97

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: rs779027563; hg19: chr17-40839856;