rs10226360

Variant names:

• chr7-147509347-A-C
• rs10226360
• NM_014141.6:c.1777+23306A>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.1777+23306A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,024 control chromosomes in the GnomAD database, including 17,480 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 0.46 (17480 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1777+23306A>C		intron_variant	Intron 11 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1777+23306A>C		intron_variant	Intron 11 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1777+23306A>C		intron_variant	Intron 11 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000636870.1	n.1639+23306A>C		intron_variant	Intron 9 of 21	5
CNTNAP2	ENST00000637825.1	n.1260+23306A>C		intron_variant	Intron 8 of 13	5
CNTNAP2	ENST00000638117.1	n.1680+23306A>C		intron_variant	Intron 10 of 12	5

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70607 AN: 151906 Hom.: 17489 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.516

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.470

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

GnomAD4 genome AF: 0.465 AC: 70616 AN: 152024 Hom.: 17480 Cov.: 32 AF XY: 0.467 AC XY: 34721 AN XY: 74286

African (AFR) AF: 0.294 AC: 12183 AN: 41496

American (AMR) AF: 0.450 AC: 6871 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1492 AN: 3472

East Asian (EAS) AF: 0.580 AC: 3000 AN: 5168

South Asian (SAS) AF: 0.653 AC: 3146 AN: 4816

European-Finnish (FIN) AF: 0.516 AC: 5432 AN: 10536

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36738 AN: 67950

Other (OTH) AF: 0.467 AC: 987 AN: 2114

Alfa AF: 0.506 Hom.: 34412

Bravo AF: 0.449

Asia WGS AF: 0.588 AC: 2044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.7
DANN	Benign	0.68
PhyloP100		1.5
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: rs10226360; hg19: chr7-147206439;