rs144056952

chr1-205069520-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PP2 PP3 BP4_Moderate BP6_Very_Strong BS1

The NM_005076.5(CNTN2):c.2155G>A(p.Gly719Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,984 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.69

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CNTN2
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.081897855).
• BP6: Variant 1-205069520-G-A is Benign according to our data. Variant chr1-205069520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000821 (125/152232) while in subpopulation NFE AF= 0.00128 (87/68026). AF 95% confidence interval is 0.00106. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN2	NM_005076.5	c.2155G>A	p.Gly719Arg	missense_variant	17/23	ENST00000331830.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN2	ENST00000331830.7	c.2155G>A	p.Gly719Arg	missense_variant	17/23	1	NM_005076.5	P1

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000961 AC: 239 AN: 248588 Hom.: 0 AF XY: 0.000973 AC XY: 131 AN XY: 134580

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00117 AC: 1711 AN: 1461752 Hom.: 3 Cov.: 31 AF XY: 0.00114 AC XY: 831 AN XY: 727168

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74430

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00100

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000873 AC: 106

EpiCase AF: 0.00180

EpiControl AF: 0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CNTN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2020

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). -

Epilepsy, familial adult myoclonic, 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.42	T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Uncertain	-0.0052	T
MutationAssessor	Pathogenic	3.5	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.73		Gain of methylation at G719 (P = 0.0258);Gain of methylation at G719 (P = 0.0258);Gain of methylation at G719 (P = 0.0258);
MVP		0.92
MPC		1.4
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.92
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144056952; hg19: chr1-205038648; COSMIC: COSV59352683; COSMIC: COSV59352683;