rs141831869

Positions:

• chr7-146839856-C-A
• chr7-146839856-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014141.6(CNTNAP2):​c.354C>A​(p.Ser118Arg) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S118S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP2 NM_014141.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0310

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.354C>A	p.Ser118Arg	missense_variant	3/24	ENST00000361727.8
CNTNAP2	XM_017011950.3	c.354C>A	p.Ser118Arg	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.354C>A	p.Ser118Arg	missense_variant	3/24	1	NM_014141.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;D;D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;.;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M;M
MutationTaster	Benign	0.60	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	.;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;D
Vest4		0.98
MutPred		0.90		Gain of MoRF binding (P = 0.0068);Gain of MoRF binding (P = 0.0068);Gain of MoRF binding (P = 0.0068);
MVP		0.96
MPC		0.54
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.91
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs141831869; hg19: chr7-146536948;