3-1278457-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1 BP6_Very_Strong

The NM_001289080.2(CNTN6):c.403C>T(p.Arg135Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,612,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: CNTN6 NM_001289080.2 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.86

Genes affected

CNTN6 (HGNC:2176): (contactin 6) The protein encoded by this gene is a member of the immunoglobulin superfamily. It is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 3-1278457-C-T is Benign according to our data. Variant chr3-1278457-C-T is described in ClinVar as [Benign]. Clinvar id is 758226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN6	NM_001289080.2	c.403C>T	p.Arg135Ter	stop_gained	5/23	ENST00000446702.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN6	ENST00000446702.7	c.403C>T	p.Arg135Ter	stop_gained	5/23	1	NM_001289080.2	P1
CNTN6	ENST00000350110.2	c.403C>T	p.Arg135Ter	stop_gained	5/23	1		P1
CNTN6	ENST00000394261.2	c.*381C>T		3_prime_UTR_variant, NMD_transcript_variant	6/8	1
CNTN6	ENST00000397479.6	c.*541C>T		3_prime_UTR_variant, NMD_transcript_variant	4/22	2

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 151972 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000522 AC: 131 AN: 251096 Hom.: 1 AF XY: 0.000508 AC XY: 69 AN XY: 135720

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1460180 Hom.: 2 Cov.: 30 AF XY: 0.000285 AC XY: 207 AN XY: 726328

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000864

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.000283 AC: 43 AN: 151972 Hom.: 0 Cov.: 33 AF XY: 0.000270 AC XY: 20 AN XY: 74204

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000998 Hom.: 1

Bravo AF: 0.000332

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000371 AC: 45

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	CNTN6: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	45
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.81	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.85
GERP RS		1.9

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: rs143789454; hg19: chr3-1320141; COSMIC: COSV63170774;