rs6808056

Variant names:

• chr3-1278503-T-C
• rs6808056
• NM_001289080.2:c.449T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349359.2(CNTN6):​c.-489T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,610,972 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (67 hom.)
• Consequence: CNTN6 NM_001349359.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.10
• Publications: 8 publications found

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]

CNTN6 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036616325).
• BP6: Variant 3-1278503-T-C is Benign according to our data. Variant chr3-1278503-T-C is described in ClinVar as Benign. ClinVar VariationId is 778061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349359.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN6	NM_001289080.2	MANE Select	c.449T>C	p.Phe150Ser	missense	Exon 5 of 23	NP_001276009.1	Q9UQ52
	CNTN6	NM_001349359.2		c.-489T>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 21	NP_001336288.1
	CNTN6	NM_001349360.2		c.-367T>C		5_prime_UTR_premature_start_codon_gain	Exon 5 of 21	NP_001336289.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN6	ENST00000446702.7	TSL:1 MANE Select	c.449T>C	p.Phe150Ser	missense	Exon 5 of 23	ENSP00000407822.2	Q9UQ52
	CNTN6	ENST00000350110.2	TSL:1	c.449T>C	p.Phe150Ser	missense	Exon 5 of 23	ENSP00000341882.2	Q9UQ52
	CNTN6	ENST00000394261.2	TSL:1	n.*427T>C		non_coding_transcript_exon	Exon 6 of 8	ENSP00000377804.2	F8WDQ0

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2341 AN: 152052 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00669

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00527 AC: 1322 AN: 250768 AF XY: 0.00400

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00221 AC: 3220 AN: 1458802 Hom.: 67 Cov.: 29 AF XY: 0.00201 AC XY: 1456 AN XY: 725600

African (AFR) AF: 0.0531 AC: 1775 AN: 33402

American (AMR) AF: 0.00443 AC: 197 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 512 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00713 AC: 41 AN: 5754

European-Non Finnish (NFE) AF: 0.000287 AC: 319 AN: 1109714

Other (OTH) AF: 0.00604 AC: 364 AN: 60260

GnomAD4 genome AF: 0.0154 AC: 2346 AN: 152170 Hom.: 64 Cov.: 33 AF XY: 0.0149 AC XY: 1108 AN XY: 74400

African (AFR) AF: 0.0506 AC: 2100 AN: 41524

American (AMR) AF: 0.00668 AC: 102 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68006

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00672 Hom.: 43

Bravo AF: 0.0175

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0511 AC: 225

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00587 AC: 713

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CNTN6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.95	N
PhyloP100		3.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.10
MVP		0.77
MPC		0.0037
ClinPred		0.017	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.66
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs6808056; hg19: chr3-1320187;