rs143877693

Positions:

• chr7-147132381-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014141.6(CNTNAP2):​c.1220A>G​(p.Asn407Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000799 in 1,613,692 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: CNTNAP2 NM_014141.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.03

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01616469).
• BP6: Variant 7-147132381-A-G is Benign according to our data. Variant chr7-147132381-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95555.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr7-147132381-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1220A>G	p.Asn407Ser	missense_variant	8/24	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1220A>G	p.Asn407Ser	missense_variant	8/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1220A>G	p.Asn407Ser	missense_variant	8/24	1	NM_014141.6	ENSP00000354778	P1

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 346 AN: 152036 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00667

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000944 AC: 237 AN: 251094 Hom.: 1 AF XY: 0.000752 AC XY: 102 AN XY: 135696

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00596

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000643 AC: 940 AN: 1461538 Hom.: 4 Cov.: 32 AF XY: 0.000626 AC XY: 455 AN XY: 727090

Gnomad4 AFR exome AF: 0.00696

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.00609

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152154 Hom.: 1 Cov.: 32 AF XY: 0.00241 AC XY: 179 AN XY: 74388

Gnomad4 AFR AF: 0.00672

Gnomad4 AMR AF: 0.000852

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.00252

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.000546

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 05, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 13, 2013	- -

Cortical dysplasia-focal epilepsy syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2020

The p.N407S variant (also known as c.1220A>G), located in coding exon 8 of the CNTNAP2 gene, results from an A to G substitution at nucleotide position 1220. The asparagine at codon 407 is replaced by serine, an amino acid with highly similar properties. This alteration has been detected in two individuals with autism spectrum disorder and two individuals with persistent developmental stuttering (Han TU et al. Neurobiol. Dis., 2014 Sep;69:23-31; Bakkaloglu B et al. Am. J. Hum. Genet., 2008 Jan;82:165-73). In addition, one functional study showed that this alteration maps to the L2 domain and is expected to have a mild effect on CNTNAP2 protein structure (Lu Z et al. J. Biol. Chem., 2016 Sep). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

CNTNAP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 14, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.6
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.72	.;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.95	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.68	N;.
REVEL	Benign	0.12
Sift	Benign	0.55	T;.
Sift4G	Benign	0.83	T;.
Polyphen		0.0030	B;B
Vest4		0.24
MVP		0.53
MPC		0.077
ClinPred		0.00099	T
GERP RS		0.69
Varity_R		0.038
gMVP		0.21

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: rs143877693; hg19: chr7-146829473;