rs1867864

Variant names:

• chr2-165323140-C-T
• rs1867864
• NM_001040142.2:c.1672-16C>T

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.1672-16C>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.303
• Publications: 15 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: Illumina, ClinGen
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.9).
• BP6: Variant 2-165323140-C-T is Benign according to our data. Variant chr2-165323140-C-T is described in ClinVar as Benign. ClinVar VariationId is 261400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040142.2. 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
	SCN2A	NM_001040142.2	MANE Select	c.1672-16C>T		intron	N/A	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.1672-16C>T		intron	N/A	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.1672-16C>T		intron	N/A	NP_001035233.1	Q99250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.1672-16C>T		intron	N/A	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.1672-16C>T		intron	N/A	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.1672-16C>T		intron	N/A	ENSP00000283256.6	Q99250-1

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

GnomAD2 exomes AF: 0.512 AC: 126984 AN: 247808 AF XY: 0.516

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 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

African (AFR) AF: 0.610 AC: 20311 AN: 33312

American (AMR) AF: 0.408 AC: 18188 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 16228 AN: 26082

East Asian (EAS) AF: 0.288 AC: 11425 AN: 39680

South Asian (SAS) AF: 0.476 AC: 40924 AN: 86038

European-Finnish (FIN) AF: 0.440 AC: 23470 AN: 53338

Middle Eastern (MID) AF: 0.572 AC: 3293 AN: 5758

European-Non Finnish (NFE) AF: 0.583 AC: 646016 AN: 1108980

Other (OTH) AF: 0.557 AC: 33536 AN: 60242

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

African (AFR) AF: 0.610 AC: 25278 AN: 41438

American (AMR) AF: 0.489 AC: 7474 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2165 AN: 3470

East Asian (EAS) AF: 0.335 AC: 1728 AN: 5154

South Asian (SAS) AF: 0.492 AC: 2361 AN: 4800

European-Finnish (FIN) AF: 0.437 AC: 4599 AN: 10536

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39073 AN: 67952

Other (OTH) AF: 0.554 AC: 1171 AN: 2112

Alfa AF: 0.571 Hom.: 69718

Bravo AF: 0.561

Asia WGS AF: 0.403 AC: 1403 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 11 (1)
-	-	1	Episodic ataxia, type 9 (1)
-	-	1	Seizures, benign familial infantile, 3 (1)
-	-	1	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.66
PhyloP100		-0.30
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: rs1867864; hg19: chr2-166179650; COSMIC: COSV51835864;