chr17-42683827-G-T

Position:

• chr17-42683827-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_003632.3(CNTNAP1):​c.74G>T​(p.Cys25Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CNTNAP1 NM_003632.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.98

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:):

CCR10 (HGNC:4474): (C-C motif chemokine receptor 10) Chemokines are a group of small (approximately 8 to 14 kD), mostly basic, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with a subset of 7-transmembrane, G protein-coupled receptors. Chemokines also play fundamental roles in the development, homeostasis, and function of the immune system, and they have effects on cells of the central nervous system as well as on endothelial cells involved in angiogenesis or angiostasis. Chemokines are divided into 2 major subfamilies, CXC and CC, based on the arrangement of the first 2 of the 4 conserved cysteine residues; the 2 cysteines are separated by a single amino acid in CXC chemokines and are adjacent in CC chemokines. CCR10 is the receptor for CCL27 (SCYA27; MIM 604833); CCR10-CCL27 interactions are involved in T cell-mediated skin inflammation (Homey et al., 2002 [PubMed 11821900]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 17-42683827-G-T is Pathogenic according to our data. Variant chr17-42683827-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1703491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP1	NM_003632.3	c.74G>T	p.Cys25Phe	missense_variant	2/24	ENST00000264638.9	NP_003623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP1	ENST00000264638.9	c.74G>T	p.Cys25Phe	missense_variant	2/24	1	NM_003632.3	ENSP00000264638	P1
CNTNAP1	ENST00000591662.1	c.74G>T	p.Cys25Phe	missense_variant, NMD_transcript_variant	2/24	1		ENSP00000466571
	ENST00000592440.1	n.364-285C>A		intron_variant, non_coding_transcript_variant		2
CCR10	ENST00000591568.1	c.-654C>A		5_prime_UTR_variant	1/2	3		ENSP00000467331

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459164 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 725984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratoire de Génétique Moléculaire, CHU Bordeaux

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.49	P
Vest4		0.63
MutPred		0.90		Gain of loop (P = 0.1069);
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40835845;