7-146116762-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.230

Publications

11 publications found

Variant links:

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

CNTNAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 link	c.-115G>A		upstream_gene_variant		ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4
CNTNAP2	XM_017011950.3 link	c.-115G>A		upstream_gene_variant			XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTNAP2	ENST00000625365.2 link	c.-115G>A	5_prime_UTR_variant	Exon 2 of 4	5		ENSP00000485955.1	A0A0D9SES4
CNTNAP2	ENST00000361727.8 link	c.-115G>A	upstream_gene_variant		1	NM_014141.6	ENSP00000354778.3	Q9UHC6-1
CNTNAP2	ENST00000637150.1 link	n.-186G>A	upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.496

AC:

75307

AN:

151814

Hom.:

18935

Cov.:

show subpopulations

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.:

AF XY:

0.515

AC XY:

156489

AN XY:

303876

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

7432

14864

22296

29728

37160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.496

AC:

75356

AN:

151932

Hom.:

18940

Cov.:

AF XY:

0.504

AC XY:

37413

AN XY:

74228

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1948

3895

5843

7790

9738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.508

Hom.:

26462

Bravo

AF:

0.487

Asia WGS

AF:

0.541

AC:

1882

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cortical dysplasia-focal epilepsy syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pitt-Hopkins-like syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.23

PromoterAI

0.17

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

Publications

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7-146116762-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over