Genetic Variant CNTN4:p.Leu17Val (chr3-2571552-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_175607.3(CNTN4):c.49C>G(p.Leu17Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CNTN4
NM_175607.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
autism spectrum disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

CNTN4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31453276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN4	NM_175607.3 link	c.49C>G	p.Leu17Val	missense_variant	Exon 4 of 25	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.49C>G	p.Leu17Val	missense_variant	Exon 4 of 25	5	NM_175607.3	ENSP00000396010.1		Q8IWV2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460266

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33432

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110588

Other (OTH)

AF:

0.0000166

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.49C>G (p.L17V) alteration is located in exon 3 (coding exon 1) of the CNTN4 gene. This alteration results from a C to G substitution at nucleotide position 49, causing the leucine (L) at amino acid position 17 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.087

.;.;T;T;.;T

Eigen

Benign

-0.043

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.47

T;T;.;.;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.31

T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Uncertain

2.0

.;.;M;M;.;M

PhyloP100

3.9

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.71

N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.20

T;T;T;T;D;T

Sift4G

Benign

0.89

T;D;T;T;T;T

Polyphen

0.0010

.;.;B;B;.;B

Vest4

0.49, 0.48, 0.46

MutPred

0.35

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.94

MPC

0.11

ClinPred

0.46

GERP RS

4.2

Varity_R

0.17

gMVP

0.50

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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3-2571552-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over