rs1268578810

chr7-147121151-C-Gchr7-147121151-C-T

Variant summary

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

The NM_014141.6(CNTNAP2):c.927C>G(p.Asp309Glu) 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 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D309D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CNTNAP2 NM_014141.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.861

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.927C>G	p.Asp309Glu	missense_variant	6/24	ENST00000361727.8
CNTNAP2	XM_017011950.3	c.927C>G	p.Asp309Glu	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.927C>G	p.Asp309Glu	missense_variant	6/24	1	NM_014141.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251060 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Benign	0.044
Eigen_PC	Benign	0.094
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.54
Sift	Benign	0.14	T;.
Sift4G	Benign	0.23	T;.
Polyphen		0.57	P;P
Vest4		0.91
MutPred		0.56		Loss of phosphorylation at Y312 (P = 0.1774);Loss of phosphorylation at Y312 (P = 0.1774);
MVP		0.82
MPC		0.34
ClinPred		0.83	D
GERP RS		4.9
Varity_R		0.20
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: rs1268578810; hg19: chr7-146818243;