NM_033655.5:c.3658C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033655.5(CNTNAP3):c.3658C>G(p.Leu1220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,533,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 49)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

CNTNAP3
NM_033655.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.752

Publications

0 publications found

Variant links:

Genes affected

CNTNAP3 (HGNC:13834): (contactin associated protein family member 3) The protein encoded by this gene belongs to the NCP family of cell-recognition molecules. This family represents a distinct subgroup of the neurexins. NCP proteins mediate neuron-glial interactions in vertebrates and glial-glial contact in invertebrates. The protein encoded by this gene may play a role in cell recognition within the nervous system. Alternatively spliced transcript variants encoding different isoforms have been described but their biological nature has not been determined. [provided by RefSeq, Jul 2008]

CNTNAP3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042993724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP3	NM_033655.5 link	c.3658C>G	p.Leu1220Val	missense_variant	Exon 22 of 24	ENST00000297668.11	NP_387504.2	Q9BZ76-1
CNTNAP3	NM_001393379.1 link	c.3415C>G	p.Leu1139Val	missense_variant	Exon 21 of 23		NP_001380308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTNAP3	ENST00000297668.11 link	c.3658C>G	p.Leu1220Val	missense_variant	Exon 22 of 24	1	NM_033655.5	ENSP00000297668.6	Q9BZ76-1
CNTNAP3	ENST00000377656.6 link	c.3415C>G	p.Leu1139Val	missense_variant	Exon 21 of 23	1		ENSP00000366884.2	A6NC89
CNTNAP3	ENST00000493965.5 link	n.274-249C>G		intron_variant	Intron 3 of 4	5
CNTNAP3	ENST00000477002.1 link	n.*113C>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000667

AC:

AN:

59954

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000565

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000652

AC:

AN:

1380816

Hom.:

Cov.:

AF XY:

0.00000441

AC XY:

AN XY:

680732

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000228

AC:

AN:

30660

American (AMR)

AF:

0.00

AC:

AN:

30826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24696

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35604

South Asian (SAS)

AF:

0.00

AC:

AN:

76646

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3988

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075044

Other (OTH)

AF:

0.0000175

AC:

AN:

57150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001384), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.397

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74512

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000192

AC:

AN:

41598

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.345

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3658C>G (p.L1220V) alteration is located in exon 22 (coding exon 22) of the CNTNAP3 gene. This alteration results from a C to G substitution at nucleotide position 3658, causing the leucine (L) at amino acid position 1220 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

0.078

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.1

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.00023

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.57

T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.043

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

0.75

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.15

N;N

REVEL

Benign

0.10

Sift

Benign

0.73

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.029

B;B

Vest4

0.066

MutPred

0.24

Gain of MoRF binding (P = 0.0776);.;

MVP

0.48

ClinPred

0.010

GERP RS

0.70

Varity_R

0.042

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_033655.5:c.3658C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over