rs373168416

Variant names:

• chr2-166056521-A-T
• rs373168416
• NM_001165963.4:c.384-21T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001165963.4(SCN1A):​c.384-21T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,505,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.04
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-166056521-A-T is Benign according to our data. Variant chr2-166056521-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 530611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000453 (613/1353746) while in subpopulation NFE AF = 0.000516 (523/1014008). AF 95% confidence interval is 0.000479. There are 0 homozygotes in GnomAdExome4. There are 278 alleles in the male GnomAdExome4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 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.384-21T>A		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.384-21T>A		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.384-21T>A		intron	N/A	NP_001340877.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.384-21T>A		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.384-21T>A		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.384-21T>A		intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000268 AC: 67 AN: 249714 AF XY: 0.000215

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000373

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000453 AC: 613 AN: 1353746 Hom.: 0 Cov.: 21 AF XY: 0.000409 AC XY: 278 AN XY: 679968

African (AFR) AF: 0.000288 AC: 9 AN: 31208

American (AMR) AF: 0.000494 AC: 22 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 39094

South Asian (SAS) AF: 0.00 AC: 0 AN: 83824

European-Finnish (FIN) AF: 0.000394 AC: 21 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.000516 AC: 523 AN: 1014008

Other (OTH) AF: 0.000669 AC: 38 AN: 56804

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74440

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.000328 AC: 5 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67980

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.000261

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SCN1A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		2.0
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs373168416; hg19: chr2-166913031;