rs142571794

Variant names:

• chr2-166045295-G-A
• rs142571794
• NM_001165963.4:c.1410C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-166045295-G-A
• chr2-166045295-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001165963.4(SCN1A):​c.1410C>T​(p.Ser470Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,614,142 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 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.791
• Publications: 1 publications found

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-166045295-G-A is Benign according to our data. Variant chr2-166045295-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212117.
• BP7: Synonymous conserved (PhyloP=0.791 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000256 (39/152274) while in subpopulation EAS AF = 0.0058 (30/5174). AF 95% confidence interval is 0.00417. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 39 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165963.4. 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
	SCN1A	NM_001165963.4	MANE Select	c.1410C>T	p.Ser470Ser	synonymous	Exon 13 of 29	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.1410C>T	p.Ser470Ser	synonymous	Exon 12 of 28	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.1410C>T	p.Ser470Ser	synonymous	Exon 11 of 27	NP_001340877.1	P35498-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.1410C>T	p.Ser470Ser	synonymous	Exon 13 of 29	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.1410C>T	p.Ser470Ser	synonymous	Exon 12 of 28	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.1410C>T	p.Ser470Ser	synonymous	Exon 10 of 26	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000394 AC: 99 AN: 250994 AF XY: 0.000405

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00403

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000252 AC: 368 AN: 1461868 Hom.: 1 Cov.: 32 AF XY: 0.000259 AC XY: 188 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00615 AC: 244 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000818 AC: 91 AN: 1112000

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74444

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000246

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	1	-	Epilepsy (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Migraine, familial hemiplegic, 3 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		0.79
Mutation Taster		=100/0	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: rs142571794; hg19: chr2-166901805;