3-1278462-A-T

Position:

• chr3-1278462-A-T

Variant summary

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

The NM_001349359.2(CNTN6):​c.-530A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000103 in 1,460,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CNTN6 NM_001349359.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN6	NM_001289080.2	c.408A>T	p.Glu136Asp	missense_variant	5/23	ENST00000446702.7	NP_001276009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN6	ENST00000446702.7	c.408A>T	p.Glu136Asp	missense_variant	5/23	1	NM_001289080.2	ENSP00000407822.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460612 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726526

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

EpiCase AF: 0.0000548

EpiControl AF: 0.00

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

Sep 29, 2023

The c.408A>T (p.E136D) alteration is located in exon 5 (coding exon 4) of the CNTN6 gene. This alteration results from a A to T substitution at nucleotide position 408, causing the glutamic acid (E) at amino acid position 136 to be replaced by an aspartic acid (D). 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	0.28
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.97	D;D
Vest4		0.41
MutPred		0.30		Loss of glycosylation at T131 (P = 0.0401);Loss of glycosylation at T131 (P = 0.0401);
MVP		0.88
MPC		0.019
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.34
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs915995227; hg19: chr3-1320146;