3-1278503-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN6	NM_001289080.2	c.449T>C	p.Phe150Ser	missense_variant	Exon 5 of 23	ENST00000446702.7	NP_001276009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN6	ENST00000446702.7	c.449T>C	p.Phe150Ser	missense_variant	Exon 5 of 23	1	NM_001289080.2	ENSP00000407822.2

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

GnomAD3 exomes AF: 0.00527 AC: 1322 AN: 250768 Hom.: 23 AF XY: 0.00400 AC XY: 542 AN XY: 135560

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 SAS exome AF: 0.0000328

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

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.0196

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.00604

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

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.00668

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00410 Hom.: 21

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CNTN6-related disorder Benign:1

Jan 13, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.95	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.16
Sift	Benign	0.44	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0010	B;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

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: rs6808056; hg19: chr3-1320187;