1-205066599-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005076.5(CNTN2):c.1975A>G(p.Asn659Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0102 in 1,613,766 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N659I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0077 ( 9 hom., cov: 32)

Exomes 𝑓: 0.010 ( 112 hom. )

Consequence

CNTN2
NM_005076.5 missense, splice_region

Scores

Splicing: ADA: 0.0006477

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.87

Publications

7 publications found

Variant links:

Genes affected

CNTN2 (HGNC:2172): (contactin 2) This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

CNTN2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
epilepsy, familial adult myoclonic, 5
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
benign adult familial myoclonic epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CNTN2 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 (MetaRNN=0.006545663).

BP6

Variant 1-205066599-A-G is Benign according to our data. Variant chr1-205066599-A-G is described in ClinVar as Benign. ClinVar VariationId is 474472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00769 (1172/152352) while in subpopulation NFE AF = 0.0106 (720/68032). AF 95% confidence interval is 0.00994. There are 9 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN2	NM_005076.5 link	c.1975A>G	p.Asn659Asp	missense_variant, splice_region_variant	Exon 15 of 23	ENST00000331830.7	NP_005067.1	Q02246A1ML24A1L3A3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN2	ENST00000331830.7 link	c.1975A>G	p.Asn659Asp	missense_variant, splice_region_variant	Exon 15 of 23	1	NM_005076.5	ENSP00000330633.4		Q02246

Frequencies

GnomAD3 genomes

AF:

0.00769

AC:

1170

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00800

AC:

2004

AN:

250608

AF XY:

0.00790

show subpopulations

Gnomad AFR exome

AF:

0.00259

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00704

GnomAD4 exome

AF:

0.0105

AC:

15285

AN:

1461414

Hom.:

112

Cov.:

AF XY:

0.0103

AC XY:

7484

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33478

American (AMR)

AF:

0.00190

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00256

AC:

221

AN:

86196

European-Finnish (FIN)

AF:

0.0260

AC:

1384

AN:

53196

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0118

AC:

13097

AN:

1111870

Other (OTH)

AF:

0.00699

AC:

422

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

830

1660

2489

3319

4149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.00769

AC:

1172

AN:

152352

Hom.:

Cov.:

AF XY:

0.00832

AC XY:

620

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41588

American (AMR)

AF:

0.00431

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0262

AC:

278

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0106

AC:

720

AN:

68032

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00925

Hom.:

Bravo

AF:

0.00607

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00776

AC:

942

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00931

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, familial adult myoclonic, 5

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CNTN2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.78

.;.;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.0065

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.58

N;N;.

PhyloP100

4.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.54

.;N;.

REVEL

Benign

0.050

Sift

Benign

0.33

.;T;.

Sift4G

Benign

1.0

.;T;.

Polyphen

0.0010

B;B;.

Vest4

0.22

MVP

0.72

MPC

0.49

ClinPred

0.011

GERP RS

3.8

Varity_R

0.093

gMVP

0.60

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00065

dbscSNV1_RF

Benign

0.15

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over