NM_014141.6:c.2280A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014141.6(CNTNAP2):c.2280A>G(p.Ser760Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,136 control chromosomes in the GnomAD database, including 19,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 5689 hom., cov: 31)

Exomes 𝑓: 0.12 ( 14116 hom. )

Consequence

CNTNAP2
NM_014141.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.377

Publications

19 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 7-147977886-A-G is Benign according to our data. Variant chr7-147977886-A-G is described in ClinVar as Benign. ClinVar VariationId is 95562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.377 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.478 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.2280A>G	p.Ser760Ser	synonymous	Exon 15 of 24	NP_054860.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.2280A>G	p.Ser760Ser	synonymous	Exon 15 of 24	ENSP00000354778.3
CNTNAP2	ENST00000455301.2	TSL:3	n.215A>G		non_coding_transcript_exon	Exon 3 of 3
CNTNAP2	ENST00000627772.2	TSL:2	n.453A>G		non_coding_transcript_exon	Exon 4 of 13

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32876

AN:

151888

Hom.:

5666

Cov.:

show subpopulations

Gnomad AFR

AF:

0.483

Gnomad AMI

AF:

0.0692

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.123

Gnomad EAS

AF:

0.188

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.0958

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.178

GnomAD2 exomes

AF:

0.143

AC:

35863

AN:

251414

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.492

Gnomad AMR exome

AF:

0.0857

Gnomad ASJ exome

AF:

0.115

Gnomad EAS exome

AF:

0.191

Gnomad FIN exome

AF:

0.0889

Gnomad NFE exome

AF:

0.107

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.122

AC:

178202

AN:

1461130

Hom.:

14116

Cov.:

AF XY:

0.122

AC XY:

88997

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.493

AC:

16485

AN:

33454

American (AMR)

AF:

0.0900

AC:

4025

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

3055

AN:

26132

East Asian (EAS)

AF:

0.200

AC:

7950

AN:

39684

South Asian (SAS)

AF:

0.177

AC:

15309

AN:

86250

European-Finnish (FIN)

AF:

0.0891

AC:

4761

AN:

53418

Middle Eastern (MID)

AF:

0.125

AC:

721

AN:

5760

European-Non Finnish (NFE)

AF:

0.106

AC:

117310

AN:

1111356

Other (OTH)

AF:

0.142

AC:

8586

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

8328

16656

24985

33313

41641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4576

9152

13728

18304

22880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.217

AC:

32951

AN:

152006

Hom.:

5689

Cov.:

AF XY:

0.212

AC XY:

15770

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.484

AC:

20015

AN:

41384

American (AMR)

AF:

0.119

AC:

1810

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

428

AN:

3468

East Asian (EAS)

AF:

0.187

AC:

966

AN:

5156

South Asian (SAS)

AF:

0.180

AC:

871

AN:

4828

European-Finnish (FIN)

AF:

0.0958

AC:

1015

AN:

10596

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.108

AC:

7366

AN:

67994

Other (OTH)

AF:

0.177

AC:

374

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1092

2184

3275

4367

5459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

320

640

960

1280

1600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.125

Hom.:

3312

Bravo

AF:

0.228

Asia WGS

AF:

0.221

AC:

769

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.106

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Cortical dysplasia-focal epilepsy syndrome (3)

not provided (2)

Inborn genetic diseases (1)

Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

5.5

(source)

DANN

Benign

0.63

PhyloP100

-0.38

Mutation Taster

=97/3

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over