rs373417440

Variant names:

• chr2-166052842-T-C
• rs373417440
• NM_001165963.4:c.694+10A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001165963.4(SCN1A):​c.694+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,606,734 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 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.632
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-166052842-T-C is Benign according to our data. Variant chr2-166052842-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93663.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000116 (169/1454574) while in subpopulation MID AF = 0.00139 (8/5740). AF 95% confidence interval is 0.000693. There are 1 homozygotes in GnomAdExome4. There are 87 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 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.694+10A>G		intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.694+10A>G		intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.694+10A>G		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.694+10A>G		intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.694+10A>G		intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.694+10A>G		intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 249596 AF XY: 0.0000815

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000116 AC: 169 AN: 1454574 Hom.: 1 Cov.: 30 AF XY: 0.000120 AC XY: 87 AN XY: 723974

African (AFR) AF: 0.000871 AC: 29 AN: 33286

American (AMR) AF: 0.000742 AC: 33 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.000231 AC: 6 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5740

European-Non Finnish (NFE) AF: 0.0000669 AC: 74 AN: 1106134

Other (OTH) AF: 0.000300 AC: 18 AN: 60062

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74394

African (AFR) AF: 0.000193 AC: 8 AN: 41540

American (AMR) AF: 0.000459 AC: 7 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67982

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000136

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.8
DANN	Benign	0.48
PhyloP100		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs373417440; hg19: chr2-166909352;