7-147559018-G-A

Variant names:

• chr7-147559018-G-A
• rs13225016
• NM_014141.6:c.1778-3120G>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.1778-3120G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,128 control chromosomes in the GnomAD database, including 4,677 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 0.23 (4677 hom., cov: 33)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.551
• Publications: 2 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

LOC107986721 (HGNC:):

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 = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1778-3120G>A		intron_variant	Intron 11 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1778-3120G>A		intron_variant	Intron 11 of 13		XP_016867439.1
LOC107986721	XR_001744999.2	n.142-397C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1778-3120G>A		intron_variant	Intron 11 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000636870.1	n.1640-3120G>A		intron_variant	Intron 9 of 21	5
CNTNAP2	ENST00000637825.1	n.1261-3120G>A		intron_variant	Intron 8 of 13	5
CNTNAP2	ENST00000638117.1	n.1681-3120G>A		intron_variant	Intron 10 of 12	5

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34415 AN: 152010 Hom.: 4673 Cov.: 33

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.237

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

GnomAD4 genome AF: 0.226 AC: 34427 AN: 152128 Hom.: 4677 Cov.: 33 AF XY: 0.223 AC XY: 16591 AN XY: 74348

African (AFR) AF: 0.0746 AC: 3098 AN: 41524

American (AMR) AF: 0.194 AC: 2967 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1077 AN: 3472

East Asian (EAS) AF: 0.247 AC: 1271 AN: 5154

South Asian (SAS) AF: 0.304 AC: 1466 AN: 4824

European-Finnish (FIN) AF: 0.268 AC: 2831 AN: 10572

Middle Eastern (MID) AF: 0.257 AC: 75 AN: 292

European-Non Finnish (NFE) AF: 0.305 AC: 20741 AN: 68000

Other (OTH) AF: 0.241 AC: 507 AN: 2106

Alfa AF: 0.242 Hom.: 624

Bravo AF: 0.212

Asia WGS AF: 0.251 AC: 872 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.9
DANN	Benign	0.24
PhyloP100		0.55
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: rs13225016; hg19: chr7-147256110;