rs10246256

Variant names:

• chr7-147857715-C-T
• rs10246256
• NM_014141.6:c.2099-45850C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014141.6(CNTNAP2):​c.2099-45850C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 152,054 control chromosomes in the GnomAD database, including 38,039 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (38039 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 13 publications found

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]

CNTNAP2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
• cortical dysplasia-focal epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014141.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.2099-45850C>T		intron	N/A	NP_054860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.2099-45850C>T		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000455301.2	TSL:3	n.34-45850C>T		intron	N/A
	CNTNAP2	ENST00000627772.2	TSL:2	n.272-45850C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107130 AN: 151936 Hom.: 38007 Cov.: 32

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.816

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.734

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.705 AC: 107210 AN: 152054 Hom.: 38039 Cov.: 32 AF XY: 0.698 AC XY: 51899 AN XY: 74324

African (AFR) AF: 0.770 AC: 31926 AN: 41470

American (AMR) AF: 0.668 AC: 10200 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.816 AC: 2833 AN: 3470

East Asian (EAS) AF: 0.633 AC: 3269 AN: 5168

South Asian (SAS) AF: 0.732 AC: 3518 AN: 4808

European-Finnish (FIN) AF: 0.587 AC: 6204 AN: 10568

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46925 AN: 67988

Other (OTH) AF: 0.736 AC: 1554 AN: 2112

Alfa AF: 0.680 Hom.: 18415

Bravo AF: 0.714

Asia WGS AF: 0.696 AC: 2424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.1
DANN	Benign	0.54
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10246256; hg19: chr7-147554807;