Genetic Variant CNTN4:p.Gln11His (chr3-2571536-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_175607.3(CNTN4):c.33A>T(p.Gln11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. Q11K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CNTN4
NM_175607.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.508

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18333161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN4	NM_175607.3 link	c.33A>T	p.Gln11His	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.33A>T	p.Gln11His	missense_variant	Exon 4 of 25	5	NM_175607.3	ENSP00000396010.1		Q8IWV2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461558

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111730

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.50

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.065

.;.;T;T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.52

T;T;.;.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.35

.;.;N;N;.;N

PhyloP100

-0.51

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.28

N;N;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.19

T;T;T;T;D;T

Sift4G

Benign

0.37

T;D;T;T;T;T

Polyphen

0.0

.;.;B;B;.;B

Vest4

0.28, 0.30, 0.28

MutPred

0.53

Loss of catalytic residue at Q11 (P = 0.1128);Loss of catalytic residue at Q11 (P = 0.1128);Loss of catalytic residue at Q11 (P = 0.1128);Loss of catalytic residue at Q11 (P = 0.1128);Loss of catalytic residue at Q11 (P = 0.1128);Loss of catalytic residue at Q11 (P = 0.1128);

MVP

0.88

MPC

0.10

ClinPred

0.19

GERP RS

-3.4

PromoterAI

0.0074

Neutral

(source)

Varity_R

0.072

gMVP

0.60

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over