rs1554440667

Variant summary

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

The NM_014141.6(CNTNAP2):ā€‹c.777A>Gā€‹(p.Ile259Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

CNTNAP2
NM_014141.6 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.318
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CNTNAP2NM_014141.6 linkuse as main transcriptc.777A>G p.Ile259Met missense_variant 6/24 ENST00000361727.8 NP_054860.1 Q9UHC6-1A0A090N7T7B2RCH4
CNTNAP2XM_017011950.3 linkuse as main transcriptc.777A>G p.Ile259Met missense_variant 6/14 XP_016867439.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CNTNAP2ENST00000361727.8 linkuse as main transcriptc.777A>G p.Ile259Met missense_variant 6/241 NM_014141.6 ENSP00000354778.3 Q9UHC6-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461474
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727034
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 26, 2021This sequence change replaces isoleucine with methionine at codon 259 of the CNTNAP2 protein (p.Ile259Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.30
T;T
Eigen
Benign
0.14
Eigen_PC
Benign
0.071
FATHMM_MKL
Benign
0.62
D
LIST_S2
Uncertain
0.93
.;D
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.61
D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.26
N;.
REVEL
Uncertain
0.43
Sift
Benign
0.040
D;.
Sift4G
Benign
0.10
T;.
Polyphen
0.96
D;D
Vest4
0.78
MutPred
0.50
Gain of disorder (P = 0.0474);Gain of disorder (P = 0.0474);
MVP
0.82
MPC
0.40
ClinPred
0.93
D
GERP RS
-0.69
Varity_R
0.11
gMVP
0.32

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554440667; hg19: chr7-146818093; API