NM_005076.5:c.223A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_005076.5(CNTN2):c.223A>G(p.Met75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,590,434 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

CNTN2
NM_005076.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.773

Publications

3 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061230958).

BP6

Variant 1-205058188-A-G is Benign according to our data. Variant chr1-205058188-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 581019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000473 (72/152264) while in subpopulation AMR AF = 0.000261 (4/15302). AF 95% confidence interval is 0.0000887. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN2	NM_005076.5 link	c.223A>G	p.Met75Val	missense_variant	Exon 4 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.223A>G	p.Met75Val	missense_variant	Exon 4 of 23	1	NM_005076.5	ENSP00000330633.4		Q02246

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000733

AC:

167

AN:

227740

AF XY:

0.000709

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000222

Gnomad ASJ exome

AF:

0.0165

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000183

Gnomad OTH exome

AF:

0.00128

GnomAD4 exome

AF:

0.000392

AC:

564

AN:

1438170

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

275

AN XY:

713394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32806

American (AMR)

AF:

0.000216

AC:

AN:

41682

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

380

AN:

24408

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81946

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.0000845

AC:

AN:

1100538

Other (OTH)

AF:

0.00136

AC:

AN:

59356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

123

154

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:

0.000473

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.000261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68016

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000802

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000544

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CNTN2: BP4, BS1 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CNTN2-related disorder

Benign:1

Jul 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epilepsy, familial adult myoclonic, 5

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.10

T;T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

.;.;D

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.63

N;N;.

PhyloP100

0.77

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.0

.;N;.

REVEL

Benign

0.074

Sift

Benign

0.23

.;T;.

Sift4G

Benign

0.59

.;T;.

Polyphen

0.0060

B;B;.

Vest4

0.11

MVP

0.59

MPC

0.43

ClinPred

0.021

GERP RS

5.3

Varity_R

0.23

gMVP

0.59

Mutation Taster

=93/7

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over