dbSNP rs142502980: CNTN2:p.Leu169Phe (chr1-205059101-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005076.5(CNTN2):c.505C>T(p.Leu169Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,614,204 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 10 hom. )

Consequence

CNTN2
NM_005076.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.717

Publications

10 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009752125).

BP6

Variant 1-205059101-C-T is Benign according to our data. Variant chr1-205059101-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445932.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00224 (342/152342) while in subpopulation NFE AF = 0.00414 (282/68034). AF 95% confidence interval is 0.00375. There are 2 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

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	UniProt
CNTN2	NM_005076.5	MANE Select	c.505C>T	p.Leu169Phe	missense	Exon 6 of 23	NP_005067.1	Q02246
CNTN2	NM_001346083.2		c.505C>T	p.Leu169Phe	missense	Exon 6 of 23	NP_001333012.1	Q02246
CNTN2	NR_144350.2		n.774C>T		non_coding_transcript_exon	Exon 6 of 23

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.505C>T	p.Leu169Phe	missense	Exon 6 of 23	ENSP00000330633.4	Q02246
CNTN2	ENST00000640428.1	TSL:5	c.505C>T	p.Leu169Phe	missense	Exon 6 of 23	ENSP00000491474.1	A0A1W2PQ11
CNTN2	ENST00000853779.1		c.505C>T	p.Leu169Phe	missense	Exon 6 of 24	ENSP00000523838.1

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

343

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00416

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00260

AC:

653

AN:

251318

AF XY:

0.00255

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00443

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00330

AC:

4827

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

2421

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33480

American (AMR)

AF:

0.00226

AC:

101

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00101

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00399

AC:

4439

AN:

1111992

Other (OTH)

AF:

0.00205

AC:

124

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

251

502

754

1005

1256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<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:

0.00224

AC:

342

AN:

152342

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41582

American (AMR)

AF:

0.00118

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00414

AC:

282

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00326

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00267

AC:

324

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CNTN2-related disorder (1)

Epilepsy, familial adult myoclonic, 5 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.0088

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.82

PhyloP100

0.72

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.7

REVEL

Benign

0.044

Sift

Benign

0.21

Sift4G

Benign

0.34

Polyphen

0.060

Vest4

0.27

MVP

0.48

MPC

0.52

ClinPred

0.016

GERP RS

4.0

PromoterAI

0.011

Neutral

(source)

Varity_R

0.36

gMVP

0.67

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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