7-148217353-G-A

Position:

• chr7-148217353-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000361727.8(CNTNAP2):​c.3076G>A​(p.Ala1026Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1026V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP2 ENST00000361727.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.194

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07233465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3076G>A	p.Ala1026Thr	missense_variant	19/24	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3076G>A	p.Ala1026Thr	missense_variant	19/24	1	NM_014141.6	ENSP00000354778	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 10, 2016

In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. Furthermore, the threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CNTNAP2-related disease. ClinVar contains an entry for this variant (Variation ID: 205278). This sequence change replaces alanine with threonine at codon 1026 of the CNTNAP2 protein (p.Ala1026Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2018

The p.A1026T variant (also known as c.3076G>A), located in coding exon 19 of the CNTNAP2 gene, results from a G to A substitution at nucleotide position 3076. The alanine at codon 1026 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2012

p.Ala1026Thr (GCC>ACC):c.3076 G>A in exon 19 of the CNTNAP2 gene (NM_014141.4). The Ala1026Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project did not identify Ala1026Thr in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The Ala1026Thr substitution is non-conservative, as a non-polar Alanine residue is replaced by a polar Threonine residue. It alters a position that is not well conserved across species and in silico algorithms predict that Ala1026Thr is not damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala1026Thr is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.43
DANN	Benign	0.76
DEOGEN2	Benign	0.060	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.34	.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.41	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.70	N;.;.
REVEL	Benign	0.10
Sift	Benign	0.39	T;.;.
Sift4G	Benign	0.45	T;.;T
Polyphen		0.011	B;B;.
Vest4		0.14
MutPred		0.39		Gain of phosphorylation at A1026 (P = 0.0202);Gain of phosphorylation at A1026 (P = 0.0202);.;
MVP		0.52
MPC		0.094
ClinPred		0.025	T
GERP RS		-1.9
Varity_R		0.030
gMVP		0.36

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: rs796052382; hg19: chr7-147914445;