Genetic Variant CNTN4:c.2512-8C>T (chr3-3042969-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_175607.3(CNTN4):c.2512-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,609,488 control chromosomes in the GnomAD database, including 44,952 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5144 hom., cov: 33)

Exomes 𝑓: 0.23 ( 39808 hom. )

Consequence

CNTN4
NM_175607.3 splice_region, intron

Scores

Splicing: ADA: 0.0001856

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.00500

Variant links:

Genes affected

CNTN4 (HGNC:2174): (contactin 4) This gene encodes a member of the contactin family of immunoglobulins. Contactins are axon-associated cell adhesion molecules that function in neuronal network formation and plasticity. The encoded protein is a glycosylphosphatidylinositol-anchored neuronal membrane protein that may play a role in the formation of axon connections in the developing nervous system. Deletion or mutation of this gene may play a role in 3p deletion syndrome and autism spectrum disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2011]

CNTN4 links:

CNTN4-AS1 (HGNC:39985): (CNTN4 antisense RNA 1)

CNTN4-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 3-3042969-C-T is Benign according to our data. Variant chr3-3042969-C-T is described in ClinVar as [Benign]. Clinvar id is 1242402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN4	NM_175607.3 link	c.2512-8C>T		splice_region_variant, intron_variant	Intron 21 of 24	ENST00000418658.6	NP_783200.1	Q8IWV2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN4	ENST00000418658.6 link	c.2512-8C>T		splice_region_variant, intron_variant	Intron 21 of 24	5	NM_175607.3	ENSP00000396010.1		Q8IWV2-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38293

AN:

151916

Hom.:

5130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.318

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.235

Gnomad ASJ

AF:

0.216

Gnomad EAS

AF:

0.113

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.265

GnomAD3 exomes

AF:

0.216

AC:

54074

AN:

249844

Hom.:

6066

AF XY:

0.214

AC XY:

28935

AN XY:

135060

show subpopulations

Gnomad AFR exome

AF:

0.322

Gnomad AMR exome

AF:

0.185

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.109

Gnomad SAS exome

AF:

0.174

Gnomad FIN exome

AF:

0.206

Gnomad NFE exome

AF:

0.241

Gnomad OTH exome

AF:

0.245

GnomAD4 exome

AF:

0.231

AC:

336726

AN:

1457454

Hom.:

39808

Cov.:

AF XY:

0.229

AC XY:

166352

AN XY:

725340

show subpopulations

Gnomad4 AFR exome

AF:

0.326

Gnomad4 AMR exome

AF:

0.191

Gnomad4 ASJ exome

AF:

0.213

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.180

Gnomad4 FIN exome

AF:

0.208

Gnomad4 NFE exome

AF:

0.238

Gnomad4 OTH exome

AF:

0.237

GnomAD4 genome

AF:

0.252

AC:

38336

AN:

152034

Hom.:

5144

Cov.:

AF XY:

0.249

AC XY:

18497

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.318

Gnomad4 AMR

AF:

0.235

Gnomad4 ASJ

AF:

0.216

Gnomad4 EAS

AF:

0.113

Gnomad4 SAS

AF:

0.165

Gnomad4 FIN

AF:

0.207

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.268

Alfa

AF:

0.246

Hom.:

3360

Bravo

AF:

0.259

Asia WGS

AF:

0.148

AC:

513

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CNTN4-related disorder

Benign:1

Jun 23, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.9

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over