rs201649365

Variant names:

• chr1-205072088-A-T
• rs201649365
• NM_005076.5:c.2686A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_005076.5(CNTN2):​c.2686A>T​(p.Thr896Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T896T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.52
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19951701).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000136 (199/1461380) while in subpopulation NFE AF = 0.000174 (194/1111906). AF 95% confidence interval is 0.000154. There are 0 homozygotes in GnomAdExome4. There are 97 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	NM_005076.5	MANE Select	c.2686A>T	p.Thr896Ser	missense	Exon 20 of 23	NP_005067.1	Q02246
	CNTN2	NM_001346083.2		c.2686A>T	p.Thr896Ser	missense	Exon 20 of 23	NP_001333012.1	Q02246
	CNTN2	NR_144350.2		n.2896A>T		non_coding_transcript_exon	Exon 20 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.2686A>T	p.Thr896Ser	missense	Exon 20 of 23	ENSP00000330633.4	Q02246
	CNTN2	ENST00000640428.1	TSL:5	c.2686A>T	p.Thr896Ser	missense	Exon 20 of 23	ENSP00000491474.1	A0A1W2PQ11
	CNTN2	ENST00000853779.1		c.2737A>T	p.Thr913Ser	missense	Exon 21 of 24	ENSP00000523838.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250690 AF XY: 0.0000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1461380 Hom.: 0 Cov.: 34 AF XY: 0.000133 AC XY: 97 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.000174 AC: 194 AN: 1111906

Other (OTH) AF: 0.0000828 AC: 5 AN: 60368

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, familial adult myoclonic, 5 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.060
Sift	Benign	0.37	T
Sift4G	Benign	0.39	T
Polyphen		0.37	B
Vest4		0.38
MutPred		0.33		Gain of glycosylation at T896 (P = 0.0225)
MVP		0.79
MPC		1.2
ClinPred		0.096	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.33
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs201649365; hg19: chr1-205041216;