rs17727261

Positions:

• chr2-124524333-C-G
• chr2-124524333-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001367498.1(CNTNAP5):​c.1358C>G​(p.Ser453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S453L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP5 NM_001367498.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP5	NM_001367498.1	c.1358C>G	p.Ser453Trp	missense_variant	9/24	ENST00000682447.1
CNTNAP5	NM_130773.4	c.1355C>G	p.Ser452Trp	missense_variant	9/24
CNTNAP5	XM_017003316.2	c.1358C>G	p.Ser453Trp	missense_variant	9/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP5	ENST00000682447.1	c.1358C>G	p.Ser453Trp	missense_variant	9/24		NM_001367498.1	A1
CNTNAP5	ENST00000431078.1	c.1355C>G	p.Ser452Trp	missense_variant	9/24	1		P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	9.0e-7	P
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.66
MutPred		0.59		Gain of MoRF binding (P = 0.03);
MVP		0.75
MPC		0.50
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.79
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17727261; hg19: chr2-125281910;