Genetic Variant CNTNAP5:p.Gly98Arg (chr2-124242304-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001367498.1(CNTNAP5):c.292G>A(p.Gly98Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,612,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CNTNAP5
NM_001367498.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.86

Publications

1 publications found

Variant links:

Genes affected

CNTNAP5 (HGNC:18748): (contactin associated protein family member 5) This gene product belongs to the neurexin family, members of which function in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, 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. [provided by RefSeq, Jul 2008]

CNTNAP5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP5	NM_001367498.1 link	c.292G>A	p.Gly98Arg	missense_variant	Exon 3 of 24	ENST00000682447.1	NP_001354427.1
CNTNAP5	NM_130773.4 link	c.292G>A	p.Gly98Arg	missense_variant	Exon 3 of 24		NP_570129.1	Q8WYK1
CNTNAP5	XM_017003316.2 link	c.292G>A	p.Gly98Arg	missense_variant	Exon 3 of 23		XP_016858805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTNAP5	ENST00000682447.1 link	c.292G>A	p.Gly98Arg	missense_variant	Exon 3 of 24		NM_001367498.1	ENSP00000508115.1	A0A804HKY0
CNTNAP5	ENST00000431078.1 link	c.292G>A	p.Gly98Arg	missense_variant	Exon 3 of 24	1		ENSP00000399013.1	Q8WYK1
CNTNAP5	ENST00000470921.1 link	n.210G>A		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000202

AC:

AN:

247140

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.0000653

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460616

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726512

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33446

American (AMR)

AF:

0.0000224

AC:

AN:

44544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39472

South Asian (SAS)

AF:

0.000116

AC:

AN:

86072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111516

Other (OTH)

AF:

0.0000497

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 10, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

PhyloP100

9.9

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.88

MutPred

0.78

Gain of MoRF binding (P = 0.03);

MVP

0.91

MPC

0.51

ClinPred

0.90

GERP RS

5.8

Varity_R

0.84

gMVP

0.53

Mutation Taster

=64/36

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

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2-124242304-G-A

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