rs41264871

Variant names:

• chr1-205066599-A-G
• rs41264871
• NM_005076.5:c.1975A>G
• CNTN2 p.Asn659Asp

Your query was ambiguous. Multiple possible variants found:

• chr1-205066599-A-G
• chr1-205066599-A-C

Variant summary

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

The NM_005076.5(CNTN2):​c.1975A>G​(p.Asn659Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0102 in 1,613,766 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N659I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 32)
  • Exomes 𝑓: 0.010 (112 hom.)
• Consequence: CNTN2 NM_005076.5 missense, splice_region
• Scores: Splicing: ADA: 0.0006477
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.87
• Publications: 7 publications found

Genes affected

CNTN2 (HGNC:2172): (contactin 2) This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

CNTN2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, familial adult myoclonic, 5

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign adult familial myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.006545663).
• BP6: Variant 1-205066599-A-G is Benign according to our data. Variant chr1-205066599-A-G is described in ClinVar as Benign. ClinVar VariationId is 474472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00769 (1172/152352) while in subpopulation NFE AF = 0.0106 (720/68032). AF 95% confidence interval is 0.00994. There are 9 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005076.5. 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
	CNTN2	NM_005076.5	MANE Select	c.1975A>G	p.Asn659Asp	missense splice_region	Exon 15 of 23	NP_005067.1	Q02246
	CNTN2	NM_001346083.2		c.1975A>G	p.Asn659Asp	missense splice_region	Exon 15 of 23	NP_001333012.1	Q02246
	CNTN2	NR_144350.2		n.2244A>G		splice_region non_coding_transcript_exon	Exon 15 of 23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTN2	ENST00000331830.7	TSL:1 MANE Select	c.1975A>G	p.Asn659Asp	missense splice_region	Exon 15 of 23	ENSP00000330633.4	Q02246
	CNTN2	ENST00000640428.1	TSL:5	c.1975A>G	p.Asn659Asp	missense splice_region	Exon 15 of 23	ENSP00000491474.1	A0A1W2PQ11
	CNTN2	ENST00000853779.1		c.2026A>G	p.Asn676Asp	missense splice_region	Exon 16 of 24	ENSP00000523838.1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152234 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00800 AC: 2004 AN: 250608 AF XY: 0.00790

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00704

GnomAD4 exome AF: 0.0105 AC: 15285 AN: 1461414 Hom.: 112 Cov.: 31 AF XY: 0.0103 AC XY: 7484 AN XY: 727000

African (AFR) AF: 0.00203 AC: 68 AN: 33478

American (AMR) AF: 0.00190 AC: 85 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00256 AC: 221 AN: 86196

European-Finnish (FIN) AF: 0.0260 AC: 1384 AN: 53196

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0118 AC: 13097 AN: 1111870

Other (OTH) AF: 0.00699 AC: 422 AN: 60384

GnomAD4 genome AF: 0.00769 AC: 1172 AN: 152352 Hom.: 9 Cov.: 32 AF XY: 0.00832 AC XY: 620 AN XY: 74494

African (AFR) AF: 0.00188 AC: 78 AN: 41588

American (AMR) AF: 0.00431 AC: 66 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0262 AC: 278 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 720 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00925 Hom.: 18

Bravo AF: 0.00607

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Epilepsy, familial adult myoclonic, 5 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.58	N
PhyloP100		4.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.050
Sift	Benign	0.33	T
Sift4G	Benign	1.0	T
Varity_R		0.093
gMVP		0.60
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00065
dbscSNV1_RF	Benign	0.15
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41264871;

hg19: chr1-205035727;

COSMIC: COSV59351026;

COSMIC: COSV59351026;