Genetic Variant CNTNAP5:p.Asn27Ile (chr2-124025730-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367498.1(CNTNAP5):c.80A>T(p.Asn27Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,459,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. N27T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CNTNAP5
NM_001367498.1 missense, splice_region

Scores

Splicing: ADA: 0.1829

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.68

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP5	NM_001367498.1 link	c.80A>T	p.Asn27Ile	missense_variant, splice_region_variant	Exon 1 of 24	ENST00000682447.1	NP_001354427.1
CNTNAP5	NM_130773.4 link	c.80A>T	p.Asn27Ile	missense_variant, splice_region_variant	Exon 1 of 24		NP_570129.1	Q8WYK1
CNTNAP5	XM_017003316.2 link	c.80A>T	p.Asn27Ile	missense_variant, splice_region_variant	Exon 1 of 23		XP_016858805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTNAP5	ENST00000682447.1 link	c.80A>T	p.Asn27Ile	missense_variant, splice_region_variant	Exon 1 of 24		NM_001367498.1	ENSP00000508115.1	A0A804HKY0
CNTNAP5	ENST00000431078.1 link	c.80A>T	p.Asn27Ile	missense_variant, splice_region_variant	Exon 1 of 24	1		ENSP00000399013.1	Q8WYK1
CNTNAP5	ENST00000423939.2 link	n.444A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248686

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459704

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726250

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110100

Other (OTH)

AF:

0.00

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.035

Eigen

Benign

0.13

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

-0.085

MutationAssessor

Benign

1.7

PhyloP100

3.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.52

Sift

Benign

0.033

Sift4G

Benign

0.067

Polyphen

0.59

Vest4

0.70

MutPred

0.47

Loss of loop (P = 0.0374);

MVP

0.67

MPC

0.27

ClinPred

0.67

GERP RS

4.3

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.23

gMVP

0.21

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.18

dbscSNV1_RF

Benign

0.45

SpliceAI score (max)

0.030

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