1-205058200-G-T

Variant names:

• chr1-205058200-G-T
• rs377098737
• NM_005076.5:c.235G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_005076.5(CNTN2):​c.235G>T​(p.Glu79*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000698 in 1,432,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CNTN2 NM_005076.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.66
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	NM_005076.5	MANE Select	c.235G>T	p.Glu79*	stop_gained	Exon 4 of 23	NP_005067.1
	CNTN2	NM_001346083.2		c.235G>T	p.Glu79*	stop_gained	Exon 4 of 23	NP_001333012.1
	CNTN2	NR_144350.2		n.504G>T		non_coding_transcript_exon	Exon 4 of 23

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.235G>T	p.Glu79*	stop_gained	Exon 4 of 23	ENSP00000330633.4
	CNTN2	ENST00000640428.1	TSL:5	c.235G>T	p.Glu79*	stop_gained	Exon 4 of 23	ENSP00000491474.1
	CNTN2	ENST00000638378.1	TSL:5	c.235G>T	p.Glu79*	stop_gained	Exon 4 of 23	ENSP00000492617.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432524 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 709674

African (AFR) AF: 0.00 AC: 0 AN: 32626

American (AMR) AF: 0.00 AC: 0 AN: 40962

Ashkenazi Jewish (ASJ) AF: 0.0000416 AC: 1 AN: 24066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 80952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097630

Other (OTH) AF: 0.00 AC: 0 AN: 59080

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.7
Vest4		0.62
GERP RS		4.4
Mutation Taster		=12/188	disease causing (fs/PTC)

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: rs377098737; hg19: chr1-205027328;