7-148259641-A-G

Variant names:

• chr7-148259641-A-G
• rs11980146
• NM_014141.6:c.3382-7392A>G

Variant summary

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

The NM_014141.6(CNTNAP2):​c.3382-7392A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,118 control chromosomes in the GnomAD database, including 9,752 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 0.35 (9752 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• 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: 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.36 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.3382-7392A>G		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.3382-7392A>G		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000628930.2	TSL:2	c.559-7392A>G		intron	N/A	ENSP00000487516.1
	CNTNAP2	ENST00000627772.2	TSL:2	n.1555-7392A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53777 AN: 152000 Hom.: 9730 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.389

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

GnomAD4 genome AF: 0.354 AC: 53827 AN: 152118 Hom.: 9752 Cov.: 32 AF XY: 0.352 AC XY: 26165 AN XY: 74368

African (AFR) AF: 0.341 AC: 14136 AN: 41498

American (AMR) AF: 0.358 AC: 5476 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1598 AN: 3468

East Asian (EAS) AF: 0.213 AC: 1101 AN: 5168

South Asian (SAS) AF: 0.239 AC: 1153 AN: 4820

European-Finnish (FIN) AF: 0.418 AC: 4420 AN: 10578

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24740 AN: 67982

Other (OTH) AF: 0.385 AC: 813 AN: 2112

Alfa AF: 0.363 Hom.: 6425

Bravo AF: 0.352

Asia WGS AF: 0.258 AC: 899 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.040
DANN	Benign	0.29
PhyloP100		-2.1
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: rs11980146; hg19: chr7-147956733;