rs79431021

Positions:

• chr1-205064390-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000331830.7(CNTN2):​c.1309C>G​(p.Leu437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,612,364 control chromosomes in the GnomAD database, including 530 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (173 hom., cov: 32)
  • Exomes 𝑓: 0.015 (357 hom.)
• Consequence: CNTN2 ENST00000331830.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.207

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNTN2. . Gene score misZ 2.5878 (greater than the threshold 3.09). Trascript score misZ 3.2882 (greater than threshold 3.09). GenCC has associacion of gene with benign adult familial myoclonic epilepsy, complex neurodevelopmental disorder, epilepsy, familial adult myoclonic, 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.001802206).
• BP6: Variant 1-205064390-C-G is Benign according to our data. Variant chr1-205064390-C-G is described in ClinVar as [Benign]. Clinvar id is 474460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN2	NM_005076.5	c.1309C>G	p.Leu437Val	missense_variant	11/23	ENST00000331830.7	NP_005067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN2	ENST00000331830.7	c.1309C>G	p.Leu437Val	missense_variant	11/23	1	NM_005076.5	ENSP00000330633	P1

Frequencies

GnomAD3 genomes AF: 0.0349 AC: 5305 AN: 152154 Hom.: 172 Cov.: 32

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0315

GnomAD3 exomes AF: 0.0179 AC: 4508 AN: 251172 Hom.: 120 AF XY: 0.0168 AC XY: 2276 AN XY: 135760

Gnomad AFR exome AF: 0.0941

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0578

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00958

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0147 AC: 21517 AN: 1460092 Hom.: 357 Cov.: 32 AF XY: 0.0146 AC XY: 10571 AN XY: 725954

Gnomad4 AFR exome AF: 0.0958

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.0579

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0232

GnomAD4 genome AF: 0.0349 AC: 5320 AN: 152272 Hom.: 173 Cov.: 32 AF XY: 0.0338 AC XY: 2517 AN XY: 74450

Gnomad4 AFR AF: 0.0895

Gnomad4 AMR AF: 0.0238

Gnomad4 ASJ AF: 0.0654

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0230 Hom.: 33

Bravo AF: 0.0410

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.0862 AC: 380

ESP6500EA AF: 0.0172 AC: 148

ExAC AF: 0.0190 AC: 2306

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Epilepsy, familial adult myoclonic, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0050
DANN	Benign	0.71
DEOGEN2	Benign	0.075	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.084	.;.;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.83	N;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.77	.;N;.
REVEL	Benign	0.059
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0	B;B;.
Vest4		0.030
MPC		0.42
ClinPred		0.00030	T
GERP RS		-7.0
Varity_R		0.024
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs79431021; hg19: chr1-205033518;