7-146254550-T-C

Variant names:

• chr7-146254550-T-C
• rs802524
• NM_014141.6:c.97+137577T>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.97+137577T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,174 control chromosomes in the GnomAD database, including 9,007 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 0.22 (9007 hom., cov: 33)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83
• Publications: 7 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.97+137577T>C		intron	N/A	NP_054860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.97+137577T>C		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000625365.2	TSL:5	c.97+137577T>C		intron	N/A	ENSP00000485955.1
	CNTNAP2	ENST00000637150.1	TSL:5	n.26+137577T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33375 AN: 152056 Hom.: 8981 Cov.: 33

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0724

Gnomad EAS AF: 0.0534

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.220 AC: 33448 AN: 152174 Hom.: 9007 Cov.: 33 AF XY: 0.214 AC XY: 15938 AN XY: 74404

African (AFR) AF: 0.643 AC: 26652 AN: 41472

American (AMR) AF: 0.110 AC: 1683 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0724 AC: 251 AN: 3468

East Asian (EAS) AF: 0.0533 AC: 276 AN: 5180

South Asian (SAS) AF: 0.121 AC: 581 AN: 4818

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10614

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.0479 AC: 3261 AN: 68018

Other (OTH) AF: 0.197 AC: 417 AN: 2114

Alfa AF: 0.0925 Hom.: 2661

Bravo AF: 0.246

Asia WGS AF: 0.118 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.077
DANN	Benign	0.46
PhyloP100		-1.8
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: rs802524; hg19: chr7-145951642;