2-124417444-C-T

Variant names:

• chr2-124417444-C-T
• rs774904439
• NM_001367498.1:c.383C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367498.1(CNTNAP5):​c.383C>T​(p.Thr128Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 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. T128N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CNTNAP5 NM_001367498.1 missense, splice_region
• Scores: Splicing: ADA: 0.00006796
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.911
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34909263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP5	NM_001367498.1	c.383C>T	p.Thr128Ile	missense_variant, splice_region_variant	Exon 4 of 24	ENST00000682447.1	NP_001354427.1
CNTNAP5	NM_130773.4	c.383C>T	p.Thr128Ile	missense_variant, splice_region_variant	Exon 4 of 24		NP_570129.1
CNTNAP5	XM_017003316.2	c.383C>T	p.Thr128Ile	missense_variant, splice_region_variant	Exon 4 of 23		XP_016858805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP5	ENST00000682447.1	c.383C>T	p.Thr128Ile	missense_variant, splice_region_variant	Exon 4 of 24		NM_001367498.1	ENSP00000508115.1
CNTNAP5	ENST00000431078.1	c.383C>T	p.Thr128Ile	missense_variant, splice_region_variant	Exon 4 of 24	1		ENSP00000399013.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Benign	0.030	N
PhyloP100		0.91
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Benign	0.035	D
Sift4G	Benign	0.22	T
Polyphen		0.52	P
Vest4		0.55
MutPred		0.61		Loss of sheet (P = 0.1398);
MVP		0.57
MPC		0.14
ClinPred		0.36	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.23
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs774904439; hg19: chr2-125175021;