rs56172264

Positions:

• chr12-40933689-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000551295.7(CNTN1):​c.804-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,612,208 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CNTN1 ENST00000551295.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004112
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.593

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-40933689-A-G is Benign according to our data. Variant chr12-40933689-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 258202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40933689-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (157/152102) while in subpopulation NFE AF= 0.00144 (98/67940). AF 95% confidence interval is 0.00121. There are 2 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.804-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.804-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001843.4	ENSP00000447006	P3

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 151984 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000461

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00125 AC: 313 AN: 250000 Hom.: 0 AF XY: 0.00129 AC XY: 174 AN XY: 135150

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00907

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000948

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00126 AC: 1843 AN: 1460106 Hom.: 2 Cov.: 31 AF XY: 0.00130 AC XY: 945 AN XY: 726378

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000628

Gnomad4 ASJ exome AF: 0.00959

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152102 Hom.: 2 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74382

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00175

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Compton-North congenital myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.032
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0060
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: rs56172264; hg19: chr12-41327491;