1-205058071-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_005076.5(CNTN2):c.215+6G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,612,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CNTN2 NM_005076.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00008703
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.262

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-205058071-G-C is Benign according to our data. Variant chr1-205058071-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541410.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000131 (20/152256) while in subpopulation NFE AF= 0.000191 (13/68040). AF 95% confidence interval is 0.000112. There are 1 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN2	NM_005076.5	c.215+6G>C		splice_donor_region_variant, intron_variant		ENST00000331830.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN2	ENST00000331830.7	c.215+6G>C		splice_donor_region_variant, intron_variant		1	NM_005076.5	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152256 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000570 AC: 14 AN: 245448 Hom.: 0 AF XY: 0.0000675 AC XY: 9 AN XY: 133424

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1460660 Hom.: 0 Cov.: 32 AF XY: 0.000145 AC XY: 105 AN XY: 726626

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152256 Hom.: 1 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74392

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000982

EpiCase AF: 0.000218

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, familial adult myoclonic, 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change falls in intron 3 of the CNTN2 gene. It does not directly change the encoded amino acid sequence of the CNTN2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370377460, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CNTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 541410). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CNTN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	3.3
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000087
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs370377460; hg19: chr1-205027199;