rs756920444

Variant names:

• chr1-205057935-C-G
• rs756920444
• NM_005076.5:c.85C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_005076.5(CNTN2):​c.85C>G​(p.Leu29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,642 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (1 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0420
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052864403).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000958 (14/1461642) while in subpopulation SAS AF = 0.000162 (14/86230). AF 95% confidence interval is 0.0000979. There are 1 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.85C>G	p.Leu29Val	missense	Exon 3 of 23	NP_005067.1	Q02246
	CNTN2	NM_001346083.2		c.85C>G	p.Leu29Val	missense	Exon 3 of 23	NP_001333012.1	Q02246
	CNTN2	NR_144350.2		n.354C>G		non_coding_transcript_exon	Exon 3 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.85C>G	p.Leu29Val	missense	Exon 3 of 23	ENSP00000330633.4	Q02246
	CNTN2	ENST00000640428.1	TSL:5	c.85C>G	p.Leu29Val	missense	Exon 3 of 23	ENSP00000491474.1	A0A1W2PQ11
	CNTN2	ENST00000853779.1		c.85C>G	p.Leu29Val	missense	Exon 3 of 24	ENSP00000523838.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250996 AF XY: 0.0000295

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: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461642 Hom.: 1 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727106

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

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	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.7
DANN	Benign	0.71
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.042
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.028
Sift	Benign	0.50	T
Sift4G	Benign	0.52	T
Polyphen		0.0040	B
Vest4		0.096
MutPred		0.31		Gain of catalytic residue at L29 (P = 0.0231)
MVP		0.53
MPC		0.43
ClinPred		0.019	T
GERP RS		1.4
Varity_R		0.033
gMVP		0.13
Mutation Taster		=99/1	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: rs756920444; hg19: chr1-205027063;