rs34326474

Variant names:

• chr12-41016821-G-A
• rs34326474
• NM_001843.4:c.2324G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-41016821-G-A
• chr12-41016821-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001843.4(CNTN1):​c.2324G>A​(p.Ser775Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,614,034 control chromosomes in the GnomAD database, including 48 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S775I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (25 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.15
• Publications: 5 publications found

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]

CNTN1 Gene-Disease associations (from GenCC):

• Compton-North congenital myopathy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043031573).
• BP6: Variant 12-41016821-G-A is Benign according to our data. Variant chr12-41016821-G-A is described in ClinVar as Benign. ClinVar VariationId is 128794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00911 (1387/152186) while in subpopulation AFR AF = 0.0311 (1289/41508). AF 95% confidence interval is 0.0296. There are 23 homozygotes in GnomAd4. There are 628 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001843.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN1	NM_001843.4	MANE Select	c.2324G>A	p.Ser775Asn	missense	Exon 19 of 24	NP_001834.2
	CNTN1	NM_175038.2		c.2291G>A	p.Ser764Asn	missense	Exon 17 of 22	NP_778203.1	Q12860-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN1	ENST00000551295.7	TSL:1 MANE Select	c.2324G>A	p.Ser775Asn	missense	Exon 19 of 24	ENSP00000447006.1	Q12860-1
	CNTN1	ENST00000347616.5	TSL:1	c.2324G>A	p.Ser775Asn	missense	Exon 18 of 23	ENSP00000325660.3	Q12860-1
	CNTN1	ENST00000348761.2	TSL:1	c.2291G>A	p.Ser764Asn	missense	Exon 17 of 22	ENSP00000261160.3	Q12860-2

Frequencies

GnomAD3 genomes AF: 0.00909 AC: 1383 AN: 152068 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00247 AC: 620 AN: 251398 AF XY: 0.00178

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000938 AC: 1371 AN: 1461848 Hom.: 25 Cov.: 32 AF XY: 0.000815 AC XY: 593 AN XY: 727224

African (AFR) AF: 0.0331 AC: 1108 AN: 33478

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111988

Other (OTH) AF: 0.00190 AC: 115 AN: 60394

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152186 Hom.: 23 Cov.: 32 AF XY: 0.00844 AC XY: 628 AN XY: 74406

African (AFR) AF: 0.0311 AC: 1289 AN: 41508

American (AMR) AF: 0.00451 AC: 69 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67996

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00422 Hom.: 27

Bravo AF: 0.0102

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00311 AC: 378

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Compton-North congenital myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.087
Sift	Benign	0.38	T
Sift4G	Benign	0.32	T
Polyphen		0.076	B
Vest4		0.14
MVP		0.35
MPC		0.32
ClinPred		0.0084	T
GERP RS		2.2
Varity_R		0.082
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs34326474; hg19: chr12-41410623; COSMIC: COSV99049753;