17-42687838-G-T

Position:

• chr17-42687838-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003632.3(CNTNAP1):​c.1163G>T​(p.Arg388Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTNAP1 NM_003632.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.33

Genes affected

CNTNAP1 (HGNC:8011): (contactin associated protein 1) The gene product was initially identified as a 190-kD protein associated with the contactin-PTPRZ1 complex. The 1,384-amino acid protein, also designated p190 or CASPR for 'contactin-associated protein,' includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that the gene is transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. The architecture of its extracellular domain is similar to that of neurexins, and this protein may be the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons. [provided by RefSeq, Jan 2009]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNTNAP1. . Gene score misZ 3.2225 (greater than the threshold 3.09). Trascript score misZ 3.8309 (greater than threshold 3.09). GenCC has associacion of gene with lethal congenital contracture syndrome 7, hypomyelination neuropathy-arthrogryposis syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP1	NM_003632.3	c.1163G>T	p.Arg388Leu	missense_variant	8/24	ENST00000264638.9	NP_003623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP1	ENST00000264638.9	c.1163G>T	p.Arg388Leu	missense_variant	8/24	1	NM_003632.3	ENSP00000264638	P1
CNTNAP1	ENST00000591662.1	c.1163G>T	p.Arg388Leu	missense_variant, NMD_transcript_variant	8/24	1		ENSP00000466571
	ENST00000592440.1	n.364-4296C>A		intron_variant, non_coding_transcript_variant		2
CNTNAP1	ENST00000586801.1	n.578G>T		non_coding_transcript_exon_variant	1/2	3

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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.86	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.017	D
Polyphen		0.32	B
Vest4		0.70
MutPred		0.66		Loss of methylation at R388 (P = 0.0216);
MVP		0.76
MPC		1.8
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.31
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs779027563; hg19: chr17-40839856; COSMIC: COSV52853552; COSMIC: COSV52853552;