7-147200311-A-G

Variant names:

• chr7-147200311-A-G
• rs10273775
• NM_014141.6:c.1348+67802A>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.1348+67802A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 151,972 control chromosomes in the GnomAD database, including 21,458 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 0.52 (21458 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.805
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1348+67802A>G		intron_variant	Intron 8 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1348+67802A>G		intron_variant	Intron 8 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1348+67802A>G		intron_variant	Intron 8 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79673 AN: 151852 Hom.: 21432 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.698

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.580

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

GnomAD4 genome AF: 0.525 AC: 79747 AN: 151972 Hom.: 21458 Cov.: 32 AF XY: 0.527 AC XY: 39184 AN XY: 74284

African (AFR) AF: 0.419 AC: 17338 AN: 41426

American (AMR) AF: 0.517 AC: 7897 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2293 AN: 3468

East Asian (EAS) AF: 0.615 AC: 3171 AN: 5156

South Asian (SAS) AF: 0.698 AC: 3358 AN: 4812

European-Finnish (FIN) AF: 0.539 AC: 5693 AN: 10564

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38076 AN: 67950

Other (OTH) AF: 0.584 AC: 1233 AN: 2110

Alfa AF: 0.544 Hom.: 76718

Bravo AF: 0.511

Asia WGS AF: 0.663 AC: 2308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.85
DANN	Benign	0.29
PhyloP100		-0.81
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: rs10273775; hg19: chr7-146897403;