rs147693556

chr1-205064636-C-Achr1-205064636-C-Gchr1-205064636-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_005076.5(CNTN2):c.1405C>A(p.Pro469Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,168 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P469S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (11 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.20

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CNTN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0072214603).
• BP6: Variant 1-205064636-C-A is Benign according to our data. Variant chr1-205064636-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474462.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00161 (245/152332) while in subpopulation AMR AF= 0.00235 (36/15298). AF 95% confidence interval is 0.00198. There are 0 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN2	NM_005076.5	c.1405C>A	p.Pro469Thr	missense_variant	12/23	ENST00000331830.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN2	ENST00000331830.7	c.1405C>A	p.Pro469Thr	missense_variant	12/23	1	NM_005076.5	P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00177 AC: 444 AN: 251302 Hom.: 0 AF XY: 0.00190 AC XY: 258 AN XY: 135800

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00271

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00213 AC: 3116 AN: 1461836 Hom.: 11 Cov.: 32 AF XY: 0.00222 AC XY: 1613 AN XY: 727226

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74494

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00227 Hom.: 2

Bravo AF: 0.00184

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00170 AC: 206

EpiCase AF: 0.00382

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, familial adult myoclonic, 5 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

CNTN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0072	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.76	N
PrimateAI	Benign	0.36	T
Polyphen		0.066	B;B;.
Vest4		0.072
MVP		0.81
MPC		0.52
ClinPred		0.0073	T
GERP RS		3.5
Varity_R		0.072
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147693556; hg19: chr1-205033764;