Genetic Variant CNTN4:p.Pro58Ala (chr3-2736331-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_175607.3(CNTN4):c.172C>G(p.Pro58Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CNTN4
NM_175607.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.78

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):

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

CNTN4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNTN4	NM_175607.3	MANE Select	c.172C>G	p.Pro58Ala	missense	Exon 5 of 25	NP_783200.1	Q8IWV2-1
CNTN4	NM_001206955.2		c.172C>G	p.Pro58Ala	missense	Exon 4 of 24	NP_001193884.1	Q8IWV2-1
CNTN4	NM_001350095.2		c.172C>G	p.Pro58Ala	missense	Exon 5 of 25	NP_001337024.1	Q8IWV2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CNTN4	ENST00000418658.6	TSL:5 MANE Select	c.172C>G	p.Pro58Ala	missense	Exon 5 of 25	ENSP00000396010.1	Q8IWV2-1
CNTN4	ENST00000397461.5	TSL:5	c.172C>G	p.Pro58Ala	missense	Exon 4 of 24	ENSP00000380602.1	Q8IWV2-1
CNTN4	ENST00000427331.5	TSL:5	c.172C>G	p.Pro58Ala	missense	Exon 2 of 22	ENSP00000413642.1	Q8IWV2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.2

PhyloP100

6.8

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.79

MutPred

0.84

Gain of MoRF binding (P = 0.037)

MVP

0.81

MPC

0.53

ClinPred

0.99

GERP RS

6.0

Varity_R

0.21

gMVP

0.82

Mutation Taster

=42/58

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over