17-42687838-G-C

Position:

chr17-42687838-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.33

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNTNAP1. . Gene score misZ 3.2225 (greater than the threshold 3.09). Trascript score misZ 3.8309 (greater than threshold 3.09). GenCC has associacion of gene with lethal congenital contracture syndrome 7, hypomyelination neuropathy-arthrogryposis syndrome.

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	Protein	UniProt
CNTNAP1	NM_003632.3 linkuse as main transcript	c.1163G>C	p.Arg388Pro	missense_variant	8/24	ENST00000264638.9	NP_003623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CNTNAP1	ENST00000264638.9 linkuse as main transcript	c.1163G>C	p.Arg388Pro	missense_variant	8/24	1	NM_003632.3	ENSP00000264638	P1
CNTNAP1	ENST00000591662.1 linkuse as main transcript	c.1163G>C	p.Arg388Pro	missense_variant, NMD_transcript_variant	8/24	1		ENSP00000466571
	ENST00000592440.1 linkuse as main transcript	n.364-4296C>G		intron_variant, non_coding_transcript_variant		2
CNTNAP1	ENST00000586801.1 linkuse as main transcript	n.578G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

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:

AN:

251460

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

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:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

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:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lethal congenital contracture syndrome 7

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jul 17, 2024	The homozygous p.Arg388Pro variant in CNTNAP1 was identified by our study in 1 individual with congenital contracture syndrome. This individual, along with another homozygous individual, were reported in the literature (PMID: 27159321, 27668699, 29882456, 31395954). This variant has been identified in 0.003% (3/60004) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779027563). This variant has also been reported in ClinVar (Variation ID: 522842) and has been interpreted as likely pathogenic by Undiagnosed Diseases Network and Ambry Genetics, and pathogenic by OMIM. Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the p.Arg388Pro variant is pathogenic (PMID: 27159321, 27668699, 29882456, 31395954). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The number of missense variants reported in CNTNAP1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. The phenotype of individuals homozygous for this variant is highly specific for lethal congenital contracture syndrome based on unique phenotype and strict clinical testing with disease (PMID: 29882456, PMID: 27668699) In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP2, PP4, PM2_supporting (Richards 2015). -
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). -

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

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.87

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.013

Polyphen

0.68

Vest4

0.91

MutPred

0.71

Loss of MoRF binding (P = 0.0084);

MVP

0.81

MPC

2.2

ClinPred

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over