rs147891446

Variant names:

• chr2-165326869-A-G
• rs147891446
• NM_001040142.2:c.2034A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040142.2(SCN2A):​c.2034A>G​(p.Thr678Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,613,978 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (80 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0120
• 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, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-165326869-A-G is Benign according to our data. Variant chr2-165326869-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00523 (796/152336) while in subpopulation SAS AF = 0.0166 (80/4830). AF 95% confidence interval is 0.0136. There are 4 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 796 AD gene.

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.2034A>G	p.Thr678Thr	synonymous	Exon 13 of 27	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.2034A>G	p.Thr678Thr	synonymous	Exon 13 of 27	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.2034A>G	p.Thr678Thr	synonymous	Exon 14 of 28	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.2034A>G	p.Thr678Thr	synonymous	Exon 13 of 27	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.2034A>G	p.Thr678Thr	synonymous	Exon 13 of 27	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.2034A>G	p.Thr678Thr	synonymous	Exon 13 of 27	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152218 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00655 AC: 1647 AN: 251352 AF XY: 0.00735

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00739

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00769 AC: 11237 AN: 1461642 Hom.: 80 Cov.: 32 AF XY: 0.00807 AC XY: 5865 AN XY: 727108

African (AFR) AF: 0.00114 AC: 38 AN: 33468

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.0185 AC: 1598 AN: 86252

European-Finnish (FIN) AF: 0.00367 AC: 196 AN: 53402

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5764

European-Non Finnish (NFE) AF: 0.00786 AC: 8741 AN: 1111856

Other (OTH) AF: 0.00624 AC: 377 AN: 60386

GnomAD4 genome AF: 0.00523 AC: 796 AN: 152336 Hom.: 4 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74488

African (AFR) AF: 0.00154 AC: 64 AN: 41578

American (AMR) AF: 0.00444 AC: 68 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4830

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00729 AC: 496 AN: 68030

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00620 Hom.: 4

Bravo AF: 0.00484

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (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	-0.51
CADD	Benign	7.8
DANN	Benign	0.81
PhyloP100		-0.012
Mutation Taster		=69/31	polymorphism

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: rs147891446; hg19: chr2-166183379;