NM_014141.6:c.97+248844T>G

Variant names:

• chr7-146365817-T-G
• rs12703803
• NM_014141.6:c.97+248844T>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.97+248844T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,068 control chromosomes in the GnomAD database, including 4,872 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 (4872 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.314
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.97+248844T>G		intron_variant	Intron 1 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.97+248844T>G		intron_variant	Intron 1 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.97+248844T>G		intron_variant	Intron 1 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000625365.2	c.97+248844T>G		intron_variant	Intron 2 of 3	5		ENSP00000485955.1
CNTNAP2	ENST00000637150.1	n.26+248844T>G		intron_variant	Intron 1 of 8	5

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34694 AN: 151948 Hom.: 4862 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.228 AC: 34713 AN: 152068 Hom.: 4872 Cov.: 32 AF XY: 0.227 AC XY: 16853 AN XY: 74340

African (AFR) AF: 0.0765 AC: 3177 AN: 41530

American (AMR) AF: 0.392 AC: 5973 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3468

East Asian (EAS) AF: 0.311 AC: 1607 AN: 5164

South Asian (SAS) AF: 0.147 AC: 708 AN: 4826

European-Finnish (FIN) AF: 0.228 AC: 2402 AN: 10556

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19186 AN: 67956

Other (OTH) AF: 0.248 AC: 525 AN: 2114

Alfa AF: 0.130 Hom.: 241

Bravo AF: 0.241

Asia WGS AF: 0.248 AC: 859 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.61
PhyloP100		0.31
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: rs12703803; hg19: chr7-146062909;