rs371816961

Positions:

• chr1-205061966-C-A
• chr1-205061966-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2 PP2 BP4_Strong BP6 BS1

The NM_005076.5(CNTN2):​c.1075C>A​(p.Arg359Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000305 in 1,612,954 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: CNTN2 NM_005076.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNTN2. . Gene score misZ 2.5878 (greater than the threshold 3.09). Trascript score misZ 3.2882 (greater than threshold 3.09). GenCC has associacion of gene with benign adult familial myoclonic epilepsy, complex neurodevelopmental disorder, epilepsy, familial adult myoclonic, 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.023443282).
• BP6: Variant 1-205061966-C-A is Benign according to our data. Variant chr1-205061966-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522750.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000177 (27/152374) while in subpopulation SAS AF= 0.00455 (22/4834). AF 95% confidence interval is 0.00308. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN2	NM_005076.5	c.1075C>A	p.Arg359Ser	missense_variant	9/23	ENST00000331830.7	NP_005067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN2	ENST00000331830.7	c.1075C>A	p.Arg359Ser	missense_variant	9/23	1	NM_005076.5	ENSP00000330633	P1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000730 AC: 181 AN: 247836 Hom.: 0 AF XY: 0.00103 AC XY: 138 AN XY: 134580

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000875

Gnomad SAS exome AF: 0.00506

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000716

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000318 AC: 465 AN: 1460580 Hom.: 1 Cov.: 30 AF XY: 0.000469 AC XY: 341 AN XY: 726600

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152374 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74512

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Epilepsy, familial adult myoclonic, 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.56	N;N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	.;D;.
REVEL	Uncertain	0.42
Sift	Benign	0.036	.;D;.
Sift4G	Benign	0.067	.;T;.
Polyphen		0.95	P;P;.
Vest4		0.84
MVP		0.86
MPC		1.2
ClinPred		0.76	D
GERP RS		5.2
Varity_R		0.72
gMVP		0.65

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: rs371816961; hg19: chr1-205031094;