rs12076297

chr1-205058028-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_005076.5(CNTN2):c.178G>A(p.Ala60Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,400 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A60V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CNTN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070005357).
• BP6: Variant 1-205058028-G-A is Benign according to our data. Variant chr1-205058028-G-A is described in ClinVar as [Benign]. Clinvar id is 474469.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1775/152278) while in subpopulation AFR AF= 0.0406 (1686/41556). AF 95% confidence interval is 0.039. There are 35 homozygotes in gnomad4. There are 841 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN2	NM_005076.5	c.178G>A	p.Ala60Thr	missense_variant	3/23	ENST00000331830.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN2	ENST00000331830.7	c.178G>A	p.Ala60Thr	missense_variant	3/23	1	NM_005076.5	P1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1766 AN: 152160 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00294 AC: 737 AN: 250328 Hom.: 15 AF XY: 0.00219 AC XY: 296 AN XY: 135446

Gnomad AFR exome AF: 0.0422

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00109 AC: 1590 AN: 1461122 Hom.: 33 Cov.: 32 AF XY: 0.000944 AC XY: 686 AN XY: 726842

Gnomad4 AFR exome AF: 0.0405

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.0117 AC: 1775 AN: 152278 Hom.: 35 Cov.: 32 AF XY: 0.0113 AC XY: 841 AN XY: 74458

Gnomad4 AFR AF: 0.0406

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00222 Hom.: 10

Bravo AF: 0.0133

ESP6500AA AF: 0.0427 AC: 188

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, familial adult myoclonic, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.53	D
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	N;N;.
MutationTaster	Benign	0.69	D
PrimateAI	Benign	0.34	T
Polyphen		0.0040	B;B;.
Vest4		0.094
MVP		0.61
MPC		0.41
ClinPred		0.012	T
GERP RS		5.4
Varity_R		0.12
gMVP		0.40

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: rs12076297; hg19: chr1-205027156; COSMIC: COSV99045549; COSMIC: COSV99045549;