rs12076297

Positions:

• chr1-205058028-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong 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. 13/20 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, multiple submitters, no conflicts B:2
• 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]

CNTN2 (HGNC:):

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=0.0070005357).
• 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_multiple_submitters_no_conflicts, 2 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. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN2	NM_005076.5	c.178G>A	p.Ala60Thr	missense_variant	3/23	ENST00000331830.7	NP_005067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN2	ENST00000331830.7	c.178G>A	p.Ala60Thr	missense_variant	3/23	1	NM_005076.5	ENSP00000330633.4

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: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	0.13
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
LIST_S2	Benign	0.77	.;.;T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.2	N;N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	.;N;.
REVEL	Benign	0.055
Sift	Benign	0.14	.;T;.
Sift4G	Benign	1.0	.;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;