NM_014141.6:c.2099-14076T>C

Variant names:

• chr7-147889489-T-C
• rs2215798
• NM_014141.6:c.2099-14076T>C

Variant summary

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

The NM_014141.6(CNTNAP2):​c.2099-14076T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 151,814 control chromosomes in the GnomAD database, including 4,076 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 0.21 (4076 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.486
• Publications: 3 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: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.2099-14076T>C		intron	N/A	NP_054860.1	A0A090N7T7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.2099-14076T>C		intron	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000455301.2	TSL:3	n.34-14076T>C		intron	N/A
	CNTNAP2	ENST00000627772.2	TSL:2	n.272-14076T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31886 AN: 151698 Hom.: 4066 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.210 AC: 31926 AN: 151814 Hom.: 4076 Cov.: 32 AF XY: 0.208 AC XY: 15429 AN XY: 74166

African (AFR) AF: 0.370 AC: 15331 AN: 41394

American (AMR) AF: 0.123 AC: 1866 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 693 AN: 3462

East Asian (EAS) AF: 0.150 AC: 775 AN: 5170

South Asian (SAS) AF: 0.152 AC: 733 AN: 4828

European-Finnish (FIN) AF: 0.171 AC: 1796 AN: 10484

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.151 AC: 10234 AN: 67932

Other (OTH) AF: 0.180 AC: 381 AN: 2112

Alfa AF: 0.173 Hom.: 1617

Bravo AF: 0.213

Asia WGS AF: 0.162 AC: 561 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.2
DANN	Benign	0.71
PhyloP100		0.49
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: rs2215798; hg19: chr7-147586581;