rs201326295

chr7-147044019-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_014141.6(CNTNAP2):c.515T>C(p.Ile172Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I172I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: CNTNAP2 NM_014141.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.00

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022970676).
• BP6: Variant 7-147044019-T-C is Benign according to our data. Variant chr7-147044019-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205308.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.515T>C	p.Ile172Thr	missense_variant	4/24	ENST00000361727.8
CNTNAP2	XM_017011950.3	c.515T>C	p.Ile172Thr	missense_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.515T>C	p.Ile172Thr	missense_variant	4/24	1	NM_014141.6	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000445 AC: 112 AN: 251442 Hom.: 1 AF XY: 0.000486 AC XY: 66 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00555

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1461840 Hom.: 2 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00335

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00482

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000252 Hom.: 0

Bravo AF: 0.000298

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2017

p.I172T (ATT>ACT): c.515T>C in CNTNAP2 gene (NM_014141.5). The Ile172Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Isoleucine residue is replaced by a polar Threonine residue. It alters a position in the F5/8 type C domain of the protein that is conserved through mammals, but Threonine is observed at this position in more distant species in evolution. Missense mutations have not been reported in this region of the protein, and multiple in silico algorithms predict Ile172Thr is likely benign. The identification of Ile172Thr an unaffected parent provided additional evidence to suggest that this variant is benign; however, the possibility that it is a disease-causing mutation cannot be excluded, as heterozygous mutations in CNTNAP2 have been identified in unaffected individuals, demonstrating incomplete penetrance (Elia et al., 2010; Gregor et al., 2011; Bakkaloglu et al., 2008; O'Roak et al., 2011; Mefford et al., 2010; Poot et al., 2010). The variant is found in INFANT-EPI,EPILEPSY panel(s). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	22
Dann	Benign	0.93
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Benign	-0.0033
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	0.70	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.025	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		0.54	P;P
Vest4		0.76
MVP		0.93
MPC		0.47
ClinPred		0.24	T
GERP RS		4.3
Varity_R		0.48
gMVP		0.75

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: rs201326295; hg19: chr7-146741111; COSMIC: COSV62183341; COSMIC: COSV62183341;