7-147120974-C-T

Variant names:

• chr7-147120974-C-T
• rs369675346
• NM_014141.6:c.755-5C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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: Splicing: ADA: 0.00001017
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:4
• Conservation: PhyloP100: -1.32

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]

ACMG classification

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, Benign=1, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.755-5C>T		splice_region_variant, intron_variant	Intron 5 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.755-5C>T		splice_region_variant, intron_variant	Intron 5 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.755-5C>T		splice_region_variant, intron_variant	Intron 5 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152184 Hom.: 0 Cov.: 32

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

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

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

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:1 Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Apr 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CNTNAP2 c.755-5C>T alters a nucleotide located at a position not widely known to affect splicing. 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. 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 observed in individual(s) affected with epilepsy (Bobbili_2018). These report(s) do 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). ClinVar contains an entry for this variant (Variation ID: 136809). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 30, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Uncertain:2

May 22, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Self-limited epilepsy with centrotemporal spikes Pathogenic:1

Jan 01, 2017

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

CAADphred>15 -

Inborn genetic diseases Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.755-5C>T intronic alteration consists of a C to T substitution 5 nucleotides before coding exon 6 in the CNTNAP2 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autism, susceptibility to, 15;C2750246:Cortical dysplasia-focal epilepsy syndrome Uncertain:1

-

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CNTNAP2 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

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Other links and lift over

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