7-146116001-A-G

Variant names:

• chr7-146116001-A-G
• rs34712024
• ENST00000625365.2:c.-318A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000625365.2(CNTNAP2):​c.-318A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 152,872 control chromosomes in the GnomAD database, including 66 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 0.025 (66 hom., cov: 32)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.27
• Publications: 5 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=-0.81).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0245 (3726/151922) while in subpopulation AFR AF = 0.0343 (1424/41460). AF 95% confidence interval is 0.0329. There are 66 homozygotes in GnomAd4. There are 1728 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-318A>G		upstream_gene_variant		5		ENSP00000485955.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3733 AN: 151802 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0436

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00625

Gnomad FIN AF: 0.00765

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0308

GnomAD4 exome AF: 0.0158 AC: 15 AN: 950 Hom.: 0 Cov.: 0 AF XY: 0.00855 AC XY: 6 AN XY: 702

African (AFR) AF: 0.0625 AC: 1 AN: 16

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 26

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34

Middle Eastern (MID) AF: 0.125 AC: 1 AN: 8

European-Non Finnish (NFE) AF: 0.0166 AC: 13 AN: 784

Other (OTH) AF: 0.00 AC: 0 AN: 62

GnomAD4 genome AF: 0.0245 AC: 3726 AN: 151922 Hom.: 66 Cov.: 32 AF XY: 0.0233 AC XY: 1728 AN XY: 74266

African (AFR) AF: 0.0343 AC: 1424 AN: 41460

American (AMR) AF: 0.0259 AC: 396 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0436 AC: 151 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00604 AC: 29 AN: 4798

European-Finnish (FIN) AF: 0.00765 AC: 81 AN: 10586

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.0228 AC: 1546 AN: 67904

Other (OTH) AF: 0.0304 AC: 64 AN: 2104

Alfa AF: 0.0170 Hom.: 12

Bravo AF: 0.0260

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.049
DANN	Benign	0.48
PhyloP100		-1.3
PromoterAI		-0.025	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34712024; hg19: chr7-145813093;