rs2462603

Variant names:

• chr7-146116762-G-A
• rs2462603
• ENST00000625365.2:c.-115G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-146116762-G-A
• chr7-146116762-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000625365.2(CNTNAP2):​c.-115G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 741,096 control chromosomes in the GnomAD database, including 97,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (18940 hom., cov: 32)
  • Exomes 𝑓: 0.51 (78432 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.230
• Publications: 11 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: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 7-146116762-G-A is Benign according to our data. Variant chr7-146116762-G-A is described in ClinVar as Benign. ClinVar VariationId is 359171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000625365.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.-115G>A		upstream_gene	N/A	NP_054860.1	A0A090N7T7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000625365.2	TSL:5	c.-115G>A		5_prime_UTR	Exon 2 of 4	ENSP00000485955.1	A0A0D9SES4
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.-115G>A		upstream_gene	N/A	ENSP00000354778.3	Q9UHC6-1
	CNTNAP2	ENST00000637150.1	TSL:5	n.-186G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75307 AN: 151814 Hom.: 18935 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.476

GnomAD4 exome AF: 0.513 AC: 302338 AN: 589164 Hom.: 78432 Cov.: 8 AF XY: 0.515 AC XY: 156489 AN XY: 303876

African (AFR) AF: 0.440 AC: 6912 AN: 15714

American (AMR) AF: 0.526 AC: 12366 AN: 23504

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 8233 AN: 15278

East Asian (EAS) AF: 0.638 AC: 20059 AN: 31434

South Asian (SAS) AF: 0.530 AC: 27605 AN: 52044

European-Finnish (FIN) AF: 0.607 AC: 18444 AN: 30374

Middle Eastern (MID) AF: 0.497 AC: 1136 AN: 2288

European-Non Finnish (NFE) AF: 0.495 AC: 192014 AN: 387882

Other (OTH) AF: 0.508 AC: 15569 AN: 30646

GnomAD4 genome AF: 0.496 AC: 75356 AN: 151932 Hom.: 18940 Cov.: 32 AF XY: 0.504 AC XY: 37413 AN XY: 74228

African (AFR) AF: 0.436 AC: 18063 AN: 41476

American (AMR) AF: 0.500 AC: 7646 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1834 AN: 3468

East Asian (EAS) AF: 0.637 AC: 3251 AN: 5100

South Asian (SAS) AF: 0.536 AC: 2583 AN: 4822

European-Finnish (FIN) AF: 0.611 AC: 6451 AN: 10566

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.500 AC: 33958 AN: 67902

Other (OTH) AF: 0.479 AC: 1007 AN: 2104

Alfa AF: 0.508 Hom.: 26462

Bravo AF: 0.487

Asia WGS AF: 0.541 AC: 1882 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cortical dysplasia-focal epilepsy syndrome (1)
-	-	1	Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.93
PhyloP100		0.23
PromoterAI		0.17	Neutral
Mutation Taster		=299/1	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: rs2462603; hg19: chr7-145813854;