1-205059589-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_005076.5(CNTN2):c.704G>A(p.Arg235Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,613,982 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

CNTN2
NM_005076.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.97

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13890278).

BP6

Variant 1-205059589-G-A is Benign according to our data. Variant chr1-205059589-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474489.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000526 (8/152110) while in subpopulation EAS AF = 0.00116 (6/5184). AF 95% confidence interval is 0.000503. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005076.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNTN2	NM_005076.5	MANE Select	c.704G>A	p.Arg235Gln	missense	Exon 7 of 23	NP_005067.1
CNTN2	NM_001346083.2		c.704G>A	p.Arg235Gln	missense	Exon 7 of 23	NP_001333012.1
CNTN2	NR_144350.2		n.973G>A		non_coding_transcript_exon	Exon 7 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.704G>A	p.Arg235Gln	missense	Exon 7 of 23	ENSP00000330633.4
CNTN2	ENST00000640428.1	TSL:5	c.704G>A	p.Arg235Gln	missense	Exon 7 of 23	ENSP00000491474.1
CNTN2	ENST00000638378.1	TSL:5	c.704G>A	p.Arg235Gln	missense	Exon 7 of 23	ENSP00000492617.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251430

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000554

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000281

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111992

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000526

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000847

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epilepsy, familial adult myoclonic, 5 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.042

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.1

PhyloP100

7.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.1

REVEL

Benign

0.20

Sift

Benign

0.28

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.87

MutPred

0.57

Loss of methylation at R235 (P = 0.0268)

MVP

0.86

MPC

1.1

ClinPred

0.68

GERP RS

5.5

PromoterAI

0.015

Neutral

(source)

Varity_R

0.58

gMVP

0.65

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over