rs1867864

Positions:

• chr2-165323140-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.1672-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,609,910 control chromosomes in the GnomAD database, including 254,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (23906 hom., cov: 31)
  • Exomes 𝑓: 0.56 (231092 hom.)
• Consequence: SCN2A NM_001040142.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.303

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-165323140-C-T is Benign according to our data. Variant chr2-165323140-C-T is described in ClinVar as [Benign]. Clinvar id is 261400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165323140-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1672-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375437.7
SCN2A	NM_001371246.1	c.1672-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1672-16C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1672-16C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84378 AN: 151820 Hom.: 23895 Cov.: 31

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.561

GnomAD3 exomes AF: 0.512 AC: 126984 AN: 247808 Hom.: 33555 AF XY: 0.516 AC XY: 69331 AN XY: 134366

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.358

Gnomad SAS exome AF: 0.470

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.575

Gnomad OTH exome AF: 0.518

GnomAD4 exome AF: 0.558 AC: 813391 AN: 1457970 Hom.: 231092 Cov.: 31 AF XY: 0.556 AC XY: 403340 AN XY: 725592

Gnomad4 AFR exome AF: 0.610

Gnomad4 AMR exome AF: 0.408

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.288

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.440

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.556 AC: 84415 AN: 151940 Hom.: 23906 Cov.: 31 AF XY: 0.547 AC XY: 40637 AN XY: 74266

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.624

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.575

Gnomad4 OTH AF: 0.554

Alfa AF: 0.573 Hom.: 43871

Bravo AF: 0.561

Asia WGS AF: 0.403 AC: 1403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 71% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 66. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Developmental and epileptic encephalopathy, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Seizures, benign familial infantile, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Episodic ataxia, type 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.66

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: rs1867864; hg19: chr2-166179650; COSMIC: COSV51835864;