7-147120974-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_014141.6(CNTNAP2):​c.755-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,613,146 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 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

CNTNAP2
NM_014141.6 splice_region, intron

Scores

2
Splicing: ADA: 0.00001017
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: -1.32
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 7-147120974-C-T is Benign according to our data. Variant chr7-147120974-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136809.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CNTNAP2NM_014141.6 linkuse as main transcriptc.755-5C>T splice_region_variant, intron_variant ENST00000361727.8 NP_054860.1 Q9UHC6-1A0A090N7T7B2RCH4
CNTNAP2XM_017011950.3 linkuse as main transcriptc.755-5C>T splice_region_variant, intron_variant XP_016867439.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CNTNAP2ENST00000361727.8 linkuse as main transcriptc.755-5C>T splice_region_variant, intron_variant 1 NM_014141.6 ENSP00000354778.3 Q9UHC6-1

Frequencies

GnomAD3 genomes
AF:
0.000315
AC:
48
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000960
GnomAD3 exomes
AF:
0.000267
AC:
67
AN:
251082
Hom.:
0
AF XY:
0.000265
AC XY:
36
AN XY:
135706
show subpopulations
Gnomad AFR exome
AF:
0.000554
Gnomad AMR exome
AF:
0.000463
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000598
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000194
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.000153
AC:
223
AN:
1460844
Hom.:
0
Cov.:
30
AF XY:
0.000144
AC XY:
105
AN XY:
726748
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000581
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.000302
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000135
Gnomad4 OTH exome
AF:
0.000216
GnomAD4 genome
AF:
0.000322
AC:
49
AN:
152302
Hom.:
0
Cov.:
32
AF XY:
0.000376
AC XY:
28
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.000950
Alfa
AF:
0.0000820
Hom.:
0
Bravo
AF:
0.000453
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000491
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxFeb 20, 2014This 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. -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 30, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 14, 2023Variant summary: CNTNAP2 c.755-5C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00027 in 251082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CNTNAP2 causing Pitt-Hopkins-Like Syndrome 1 (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.755-5C>T has been reported in the literature in an individual affected with Rolandic epilepsy (Bobbili_2018). This report does not provide unequivocal conclusions about association of the variant with Pitt-Hopkins-Like Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29358611). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including uncertain significance (n=4), pathogenic (n=1) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsMay 22, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 24, 2017- -
Childhood epilepsy with centrotemporal spikes Pathogenic:1
Pathogenic, no assertion criteria providedcase-controlBioinformatics Core, Luxembourg Center for Systems BiomedicineJan 01, 2017CAADphred>15 -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2017The c.755-5C>T intronic variant results from a C to T substitution 5 nucleotides upstream from exon 6 in the CNTNAP2 gene. This nucleotide position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Autism, susceptibility to, 15;C2750246:Cortical dysplasia-focal epilepsy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021CNTNAP2 NM_014141.5 exon 6 c.755-5C>T: This variant has not been reported in the literature but is present in 23/126370 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs369675346). This variant is present in ClinVar (Variation ID:136809). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant; splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Cortical dysplasia-focal epilepsy syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
4.8
DANN
Benign
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000010
dbscSNV1_RF
Benign
0.0080
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.

Other links and lift over

dbSNP: rs369675346; hg19: chr7-146818066; COSMIC: COSV62206500; API