rs2195144

Variant names:

• chr2-166053241-T-C
• rs2195144
• NM_001165963.4:c.603-298A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001165963.4(SCN1A):​c.603-298A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 612,058 control chromosomes in the GnomAD database, including 158,501 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.74 (41715 hom., cov: 31)
  • Exomes 𝑓: 0.71 (116786 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.400
• Publications: 5 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

Specifications for SCN1A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

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.603-298A>G		intron	N/A	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.603-298A>G		intron	N/A	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.603-298A>G		intron	N/A	NP_001340877.1	P35498-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.603-298A>G		intron	N/A	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.603-298A>G		intron	N/A	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.603-298A>G		intron	N/A	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.738 AC: 111892 AN: 151684 Hom.: 41670 Cov.: 31

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.756

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.708 AC: 325926 AN: 460256 Hom.: 116786 AF XY: 0.704 AC XY: 171925 AN XY: 244362

African (AFR) AF: 0.821 AC: 10180 AN: 12402

American (AMR) AF: 0.775 AC: 14735 AN: 19020

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 8332 AN: 13840

East Asian (EAS) AF: 0.893 AC: 27974 AN: 31320

South Asian (SAS) AF: 0.688 AC: 30223 AN: 43914

European-Finnish (FIN) AF: 0.750 AC: 26761 AN: 35700

Middle Eastern (MID) AF: 0.521 AC: 1030 AN: 1978

European-Non Finnish (NFE) AF: 0.683 AC: 188580 AN: 275906

Other (OTH) AF: 0.692 AC: 18111 AN: 26176

GnomAD4 genome AF: 0.738 AC: 111999 AN: 151802 Hom.: 41715 Cov.: 31 AF XY: 0.741 AC XY: 54984 AN XY: 74190

African (AFR) AF: 0.824 AC: 34128 AN: 41426

American (AMR) AF: 0.742 AC: 11278 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2090 AN: 3470

East Asian (EAS) AF: 0.890 AC: 4586 AN: 5150

South Asian (SAS) AF: 0.709 AC: 3410 AN: 4808

European-Finnish (FIN) AF: 0.756 AC: 7992 AN: 10570

Middle Eastern (MID) AF: 0.517 AC: 151 AN: 292

European-Non Finnish (NFE) AF: 0.683 AC: 46334 AN: 67868

Other (OTH) AF: 0.684 AC: 1443 AN: 2110

Alfa AF: 0.717 Hom.: 5093

Bravo AF: 0.741

Asia WGS AF: 0.789 AC: 2743 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.73
PhyloP100		-0.40
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: rs2195144; hg19: chr2-166909751;