rs139732336

Positions:

• chr1-205061394-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005076.5(CNTN2):​c.947C>T​(p.Thr316Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,612,648 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T316T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (39 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.17

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.006309241).
• BP6: Variant 1-205061394-C-T is Benign according to our data. Variant chr1-205061394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474493.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00449 (684/152304) while in subpopulation NFE AF= 0.00629 (428/68010). AF 95% confidence interval is 0.0058. There are 6 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN2	NM_005076.5	c.947C>T	p.Thr316Ile	missense_variant	8/23	ENST00000331830.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN2	ENST00000331830.7	c.947C>T	p.Thr316Ile	missense_variant	8/23	1	NM_005076.5	P1

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 684 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00497 AC: 1221 AN: 245696 Hom.: 6 AF XY: 0.00461 AC XY: 613 AN XY: 133074

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000198

Gnomad FIN exome AF: 0.0139

Gnomad NFE exome AF: 0.00691

Gnomad OTH exome AF: 0.00569

GnomAD4 exome AF: 0.00601 AC: 8773 AN: 1460344 Hom.: 39 Cov.: 31 AF XY: 0.00586 AC XY: 4256 AN XY: 726338

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00287

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000500

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.00669

Gnomad4 OTH exome AF: 0.00486

GnomAD4 genome AF: 0.00449 AC: 684 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74462

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0128

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00582 Hom.: 9

Bravo AF: 0.00368

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00477 AC: 579

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2017

- -

Epilepsy, familial adult myoclonic, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
Polyphen		0.0020	B;B;.
Vest4		0.22
MVP		0.82
MPC		0.55
ClinPred		0.0062	T
GERP RS		2.1
Varity_R		0.13
gMVP		0.48

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: rs139732336; hg19: chr1-205030522; COSMIC: COSV59352869; COSMIC: COSV59352869;