chr7-146778222-G-A

Variant names:

• chr7-146778222-G-A
• rs10244837
• NM_014141.6:c.208+3841G>A

Variant summary

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

The NM_014141.6(CNTNAP2):​c.208+3841G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 152,006 control chromosomes in the GnomAD database, including 16,525 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 0.42 (16525 hom., cov: 33)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.643
• Publications: 4 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 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.208+3841G>A		intron	N/A	NP_054860.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.208+3841G>A		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000625365.2	TSL:5	c.208+3841G>A		intron	N/A	ENSP00000485955.1
	CNTNAP2	ENST00000636277.1	TSL:5	n.75+3841G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63950 AN: 151888 Hom.: 16478 Cov.: 33

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.321

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.403

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

GnomAD4 genome AF: 0.421 AC: 64055 AN: 152006 Hom.: 16525 Cov.: 33 AF XY: 0.421 AC XY: 31298 AN XY: 74290

African (AFR) AF: 0.733 AC: 30402 AN: 41472

American (AMR) AF: 0.277 AC: 4237 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1213 AN: 3458

East Asian (EAS) AF: 0.424 AC: 2191 AN: 5166

South Asian (SAS) AF: 0.374 AC: 1794 AN: 4802

European-Finnish (FIN) AF: 0.389 AC: 4103 AN: 10538

Middle Eastern (MID) AF: 0.341 AC: 99 AN: 290

European-Non Finnish (NFE) AF: 0.279 AC: 18944 AN: 67976

Other (OTH) AF: 0.401 AC: 846 AN: 2112

Alfa AF: 0.373 Hom.: 1586

Bravo AF: 0.425

Asia WGS AF: 0.396 AC: 1375 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.6
DANN	Benign	0.39
PhyloP100		0.64
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: rs10244837; hg19: chr7-146475314;