dbSNP rs34251012: CNTNAP4:p.Leu276Val (chr16-76448850-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_033401.5(CNTNAP4):c.826C>G(p.Leu276Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,613,098 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.031 ( 98 hom., cov: 31)

Exomes 𝑓: 0.022 ( 536 hom. )

Consequence

CNTNAP4
NM_033401.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

Publications

10 publications found

Variant links:

Genes affected

CNTNAP4 (HGNC:18747): (contactin associated protein family member 4) This gene encodes a member of the neurexin protein family. Members of this family function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, and thrombospondin N-terminal-like domains. This protein may also play a role in proper neurotransmission in the dopaminergic and GABAergic systems and mutations in this gene may be associated with certain psychiatric illnesses. A polymorphism in an intron of this gene may be associated with longevity. [provided by RefSeq, Apr 2016]

CNTNAP4 links:

ENSG00000287694 (HGNC:):

ENSG00000287694 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036981702).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP4	NM_033401.5 link	c.826C>G	p.Leu276Val	missense_variant	Exon 6 of 24	ENST00000611870.5	NP_207837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP4	ENST00000611870.5 link	c.826C>G	p.Leu276Val	missense_variant	Exon 6 of 24	1	NM_033401.5	ENSP00000479811.1
ENSG00000287694	ENST00000655556.1 link	n.826C>G		non_coding_transcript_exon_variant	Exon 6 of 25			ENSP00000499374.1

Frequencies

GnomAD3 genomes

AF:

0.0308

AC:

4686

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0580

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0226

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0528

Gnomad FIN

AF:

0.00737

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0197

Gnomad OTH

AF:

0.0378

GnomAD2 exomes

AF:

0.0247

AC:

6163

AN:

249732

AF XY:

0.0250

show subpopulations

Gnomad AFR exome

AF:

0.0603

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0397

Gnomad EAS exome

AF:

0.00290

Gnomad FIN exome

AF:

0.00856

Gnomad NFE exome

AF:

0.0183

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.0216

AC:

31530

AN:

1460920

Hom.:

536

Cov.:

AF XY:

0.0226

AC XY:

16416

AN XY:

726654

show subpopulations

African (AFR)

AF:

0.0613

AC:

2053

AN:

33472

American (AMR)

AF:

0.0153

AC:

685

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.0376

AC:

982

AN:

26112

East Asian (EAS)

AF:

0.00141

AC:

AN:

39650

South Asian (SAS)

AF:

0.0580

AC:

4993

AN:

86024

European-Finnish (FIN)

AF:

0.00935

AC:

499

AN:

53388

Middle Eastern (MID)

AF:

0.0272

AC:

157

AN:

5768

European-Non Finnish (NFE)

AF:

0.0184

AC:

20471

AN:

1111494

Other (OTH)

AF:

0.0271

AC:

1634

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1468

2937

4405

5874

7342

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

816

1632

2448

3264

4080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0308

AC:

4688

AN:

152178

Hom.:

Cov.:

AF XY:

0.0301

AC XY:

2242

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.0580

AC:

2407

AN:

41524

American (AMR)

AF:

0.0226

AC:

345

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3470

East Asian (EAS)

AF:

0.00348

AC:

AN:

5178

South Asian (SAS)

AF:

0.0529

AC:

255

AN:

4822

European-Finnish (FIN)

AF:

0.00737

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0197

AC:

1342

AN:

68004

Other (OTH)

AF:

0.0374

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

227

454

682

909

1136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0214

Hom.:

Bravo

AF:

0.0326

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.0607

AC:

267

ESP6500EA

AF:

0.0187

AC:

161

ExAC

AF:

0.0261

AC:

3167

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.085

T;T;T;.;.;.

Eigen

Benign

-0.011

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.83

T;T;T;T;T;T

MetaRNN

Benign

0.0037

T;T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

.;.;.;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.41

.;.;.;.;T;T

Sift4G

Benign

0.50

T;T;T;T;T;T

Polyphen

0.40

B;.;.;.;.;B

Vest4

0.30

MPC

0.026

ClinPred

0.0088

GERP RS

4.4

Varity_R

0.13

gMVP

0.17

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over