12-40933864-G-T

Position:

• chr12-40933864-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001843.4(CNTN1):​c.971G>T​(p.Arg324Ile) 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 1,458,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49

Genes affected

CNTN1 (HGNC:2171): (contactin 1) 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. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.971G>T	p.Arg324Ile	missense_variant	9/24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.971G>T	p.Arg324Ile	missense_variant	9/24	1	NM_001843.4	ENSP00000447006	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249586 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

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: 1458996 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.83	.;D;.;D;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.7	L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.29	B;P;B;P;P
Vest4		0.71
MutPred		0.64		Loss of disorder (P = 0.0444);Loss of disorder (P = 0.0444);Loss of disorder (P = 0.0444);Loss of disorder (P = 0.0444);.;
MVP		0.57
MPC		0.68
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.42
gMVP		0.75

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: rs148624625; hg19: chr12-41327666; COSMIC: COSV61641574;