2-166042428-TA-T

Variant names:

• chr2-166042428-TA-T
• rs549232924
• NM_001165963.4:c.2044-5delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001165963.4(SCN1A):​c.2044-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,577,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SCN1A NM_001165963.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.278
• 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.

• BP6: Variant 2-166042428-TA-T is Benign according to our data. Variant chr2-166042428-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 331892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	NM_001165963.4	MANE Select	c.2044-5delT		splice_region intron	N/A	NP_001159435.1
	SCN1A	NM_001202435.3		c.2044-5delT		splice_region intron	N/A	NP_001189364.1
	SCN1A	NM_001353948.2		c.2044-5delT		splice_region intron	N/A	NP_001340877.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN1A	ENST00000674923.1	MANE Select	c.2044-5delT		splice_region intron	N/A	ENSP00000501589.1
	SCN1A	ENST00000303395.9	TSL:5	c.2044-5delT		splice_region intron	N/A	ENSP00000303540.4
	SCN1A	ENST00000375405.7	TSL:5	c.2011-5delT		splice_region intron	N/A	ENSP00000364554.3

Frequencies

GnomAD3 genomes AF: 0.0000463 AC: 7 AN: 151106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000886

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000232 AC: 53 AN: 228492 AF XY: 0.000259

Gnomad AFR exome AF: 0.0000664

Gnomad AMR exome AF: 0.000326

Gnomad ASJ exome AF: 0.000322

Gnomad EAS exome AF: 0.0000598

Gnomad FIN exome AF: 0.000362

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000156 AC: 223 AN: 1425878 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 106 AN XY: 709788

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000215 AC: 7 AN: 32584

American (AMR) AF: 0.000228 AC: 10 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.000197 AC: 5 AN: 25388

East Asian (EAS) AF: 0.000182 AC: 7 AN: 38370

South Asian (SAS) AF: 0.0000826 AC: 7 AN: 84786

European-Finnish (FIN) AF: 0.000251 AC: 13 AN: 51774

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5628

European-Non Finnish (NFE) AF: 0.000156 AC: 169 AN: 1084750

Other (OTH) AF: 0.0000680 AC: 4 AN: 58812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000463 AC: 7 AN: 151218 Hom.: 0 Cov.: 33 AF XY: 0.0000677 AC XY: 5 AN XY: 73884

African (AFR) AF: 0.00 AC: 0 AN: 41248

American (AMR) AF: 0.00 AC: 0 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10378

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

European-Non Finnish (NFE) AF: 0.0000886 AC: 6 AN: 67728

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Familial hemiplegic migraine (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs549232924; hg19: chr2-166898938; COSMIC: COSV57659528;