rs1362090710

Variant names:

• chr1-205064672-T-C
• rs1362090710
• NM_005076.5:c.1441T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005076.5(CNTN2):​c.1441T>C​(p.Ser481Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1441T>C	p.Ser481Pro	missense	Exon 12 of 23	NP_005067.1	Q02246
	CNTN2	NM_001346083.2		c.1441T>C	p.Ser481Pro	missense	Exon 12 of 23	NP_001333012.1	Q02246
	CNTN2	NR_144350.2		n.1710T>C		non_coding_transcript_exon	Exon 12 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.1441T>C	p.Ser481Pro	missense	Exon 12 of 23	ENSP00000330633.4	Q02246
	CNTN2	ENST00000640428.1	TSL:5	c.1441T>C	p.Ser481Pro	missense	Exon 12 of 23	ENSP00000491474.1	A0A1W2PQ11
	CNTN2	ENST00000853779.1		c.1492T>C	p.Ser498Pro	missense	Exon 13 of 24	ENSP00000523838.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251078 AF XY: 0.00000737

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, familial adult myoclonic, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.027	D
Polyphen		0.98	D
Vest4		0.55
MutPred		0.47		Loss of stability (P = 0.0494)
MVP		0.93
MPC		1.4
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.67
gMVP		0.90
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs1362090710; hg19: chr1-205033800;