rs77025884

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_014141.6(CNTNAP2):c.3716-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 151,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CNTNAP2
NM_014141.6 splice_region, intron

Scores

Splicing: ADA: 0.0006471

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -0.317

Variant links:

Genes affected

CNTNAP2 (HGNC:13830): (contactin associated protein 2) This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains and a putative PDZ binding site. This protein is localized at the juxtaparanodes of myelinated axons, and mediates interactions between neurons and glia during nervous system development and is also involved in localization of potassium channels within differentiating axons. This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome. It is directly bound and regulated by forkhead box protein P2, a transcription factor related to speech and language development. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD and intellectual disability. [provided by RefSeq, Jul 2017]

CNTNAP2 links:

CNTNAP2 (HGNC:):

CNTNAP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 7-148409385-C-G is Benign according to our data. Variant chr7-148409385-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95572.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=7}. Variant chr7-148409385-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.3716-6C>G		splice_region_variant, intron_variant		ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4
LOC105375554	XR_928094.2 linkuse as main transcript	n.210-14693G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.3716-6C>G		splice_region_variant, intron_variant		1	NM_014141.6	ENSP00000354778.3		Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000590

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0747

AC:

11991

AN:

160516

Hom.:

3111

AF XY:

0.0766

AC XY:

6616

AN XY:

86376

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.0366

Gnomad ASJ exome

AF:

0.0527

Gnomad EAS exome

AF:

0.0558

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0738

Gnomad NFE exome

AF:

0.0763

Gnomad OTH exome

AF:

0.0789

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000130

AC:

188

AN:

1445454

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

720032

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000582

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.0000669

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151504

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73988

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000590

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.245

Hom.:

660

Bravo

AF:

0.550

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cortical dysplasia-focal epilepsy syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autism, susceptibility to, 15;C2750246:Cortical dysplasia-focal epilepsy syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CNTNAP2 NM_014141 exon 23 c.3716-6C>G: This variant has not been reported in the literature but is present in 12% (1198/9918) of African individuals, including 400 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs374969707). This variant is present in ClinVar, with several labs classifying this variant as benign (Variation ID: 95572). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as Likely Benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.3

DANN

Benign

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00065

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.12

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