chr3-1278437-C-T

Variant names:

• chr3-1278437-C-T
• rs115904769
• NM_001289080.2:c.383C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001289080.2(CNTN6):​c.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,608,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CNTN6 NM_001289080.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.04
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010070175).
• BP6: Variant 3-1278437-C-T is Benign according to our data. Variant chr3-1278437-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3044328.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 185 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289080.2. 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.383C>T	p.Thr128Ile	missense	Exon 5 of 23	NP_001276009.1	Q9UQ52
	CNTN6	NM_001349350.2		c.383C>T	p.Thr128Ile	missense	Exon 7 of 25	NP_001336279.1	Q9UQ52
	CNTN6	NM_001349351.2		c.383C>T	p.Thr128Ile	missense	Exon 7 of 25	NP_001336280.1	Q9UQ52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN6	ENST00000446702.7	TSL:1 MANE Select	c.383C>T	p.Thr128Ile	missense	Exon 5 of 23	ENSP00000407822.2	Q9UQ52
	CNTN6	ENST00000350110.2	TSL:1	c.383C>T	p.Thr128Ile	missense	Exon 5 of 23	ENSP00000341882.2	Q9UQ52
	CNTN6	ENST00000394261.2	TSL:1	n.*361C>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000377804.2	F8WDQ0

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152058 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000289 AC: 72 AN: 249480 AF XY: 0.000215

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1455984 Hom.: 0 Cov.: 30 AF XY: 0.0000857 AC XY: 62 AN XY: 723692

African (AFR) AF: 0.00405 AC: 135 AN: 33322

American (AMR) AF: 0.000113 AC: 5 AN: 44206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108176

Other (OTH) AF: 0.000200 AC: 12 AN: 60092

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.00112 AC XY: 83 AN XY: 74398

African (AFR) AF: 0.00429 AC: 178 AN: 41538

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000464 Hom.: 0

Bravo AF: 0.00135

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CNTN6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.053
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.32	B
Vest4		0.20
MVP		0.79
MPC		0.0070
ClinPred		0.047	T
GERP RS		4.1
Varity_R		0.17
gMVP		0.39
Mutation Taster		=90/10	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: rs115904769; hg19: chr3-1320121;