3-1295612-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001289080.2(CNTN6):c.466G>A(p.Ala156Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNTN6 NM_001289080.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22200811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN6	NM_001289080.2	c.466G>A	p.Ala156Thr	missense_variant	6/23	ENST00000446702.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN6	ENST00000446702.7	c.466G>A	p.Ala156Thr	missense_variant	6/23	1	NM_001289080.2	P1
CNTN6	ENST00000350110.2	c.466G>A	p.Ala156Thr	missense_variant	6/23	1		P1
CNTN6	ENST00000394261.2	c.*444G>A		3_prime_UTR_variant, NMD_transcript_variant	7/8	1
CNTN6	ENST00000397479.6	c.*604G>A		3_prime_UTR_variant, NMD_transcript_variant	5/22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248530 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726760

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.466G>A (p.A156T) alteration is located in exon 6 (coding exon 5) of the CNTN6 gene. This alteration results from a G to A substitution at nucleotide position 466, causing the alanine (A) at amino acid position 156 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.096	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.62	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.41	N;N
MutationTaster	Benign	0.71	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.097
Sift	Benign	0.69	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.10	B;B
Vest4		0.22
MutPred		0.58		Loss of catalytic residue at A156 (P = 0.0048);Loss of catalytic residue at A156 (P = 0.0048);
MVP		0.71
MPC		0.0050
ClinPred		0.22	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.46

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: rs769833336; hg19: chr3-1337296;