chr2-165313563-A-G

Variant names:

• chr2-165313563-A-G
• rs13025009
• NM_001040142.2:c.1035-57A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.1035-57A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,602,620 control chromosomes in the GnomAD database, including 32,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2356 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30638 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.530
• Publications: 4 publications found

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]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  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 (BayesDel_noAF=-0.84).
• BP6: Variant 2-165313563-A-G is Benign according to our data. Variant chr2-165313563-A-G is described in ClinVar as [Benign]. Clinvar id is 670843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.1035-57A>G		intron_variant	Intron 8 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.1035-57A>G		intron_variant	Intron 8 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.1035-57A>G		intron_variant	Intron 8 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.1035-57A>G		intron_variant	Intron 8 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.1035-57A>G		intron_variant	Intron 8 of 26	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.1035-57A>G		intron_variant	Intron 8 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23778 AN: 151934 Hom.: 2358 Cov.: 32

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.201 AC: 290843 AN: 1450566 Hom.: 30638 AF XY: 0.203 AC XY: 146593 AN XY: 722312

African (AFR) AF: 0.0518 AC: 1724 AN: 33262

American (AMR) AF: 0.197 AC: 8766 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 7838 AN: 25976

East Asian (EAS) AF: 0.103 AC: 4092 AN: 39614

South Asian (SAS) AF: 0.236 AC: 20320 AN: 86016

European-Finnish (FIN) AF: 0.0907 AC: 4836 AN: 53292

Middle Eastern (MID) AF: 0.233 AC: 1329 AN: 5716

European-Non Finnish (NFE) AF: 0.209 AC: 229845 AN: 1102112

Other (OTH) AF: 0.202 AC: 12093 AN: 60004

GnomAD4 genome AF: 0.156 AC: 23763 AN: 152054 Hom.: 2356 Cov.: 32 AF XY: 0.153 AC XY: 11380 AN XY: 74328

African (AFR) AF: 0.0543 AC: 2252 AN: 41496

American (AMR) AF: 0.193 AC: 2943 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1050 AN: 3472

East Asian (EAS) AF: 0.144 AC: 742 AN: 5154

South Asian (SAS) AF: 0.238 AC: 1146 AN: 4814

European-Finnish (FIN) AF: 0.0750 AC: 794 AN: 10586

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.209 AC: 14174 AN: 67960

Other (OTH) AF: 0.189 AC: 398 AN: 2110

Alfa AF: 0.197 Hom.: 1543

Bravo AF: 0.159

Asia WGS AF: 0.174 AC: 608 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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: rs13025009; hg19: chr2-166170073; COSMIC: COSV51832709; COSMIC: COSV51832709;