3-1227901-C-A

Variant names:

• chr3-1227901-C-A
• rs2094305042
• NM_001289080.2:c.266C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001289080.2(CNTN6):​c.266C>A​(p.Pro89His) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNTN6 NM_001289080.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN6	NM_001289080.2	c.266C>A	p.Pro89His	missense_variant	Exon 4 of 23	ENST00000446702.7	NP_001276009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN6	ENST00000446702.7	c.266C>A	p.Pro89His	missense_variant	Exon 4 of 23	1	NM_001289080.2	ENSP00000407822.2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

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: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74212

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.266C>A (p.P89H) alteration is located in exon 4 (coding exon 3) of the CNTN6 gene. This alteration results from a C to A substitution at nucleotide position 266, causing the proline (P) at amino acid position 89 to be replaced by a histidine (H). 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	Pathogenic	0.94
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.53
MutPred		0.73		Gain of catalytic residue at P89 (P = 0.0274);Gain of catalytic residue at P89 (P = 0.0274);
MVP		0.84
MPC		0.020
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.64
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2094305042; hg19: chr3-1269585;