2-166042428-TA-TAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001165963.4(SCN1A):​c.2044-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000601 in 1,580,304 control chromosomes in the GnomAD database, including 7 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SCN1A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: SCN1A NM_001165963.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• 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

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-166042428-T-TA is Benign according to our data. Variant chr2-166042428-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194032.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000311 (47/151226) while in subpopulation SAS AF = 0.00417 (20/4792). AF 95% confidence interval is 0.00277. There are 1 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 47 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.2044-5dupT		splice_region intron	N/A	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.2044-5dupT		splice_region intron	N/A	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.2044-5dupT		splice_region 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.2044-5_2044-4insT		splice_region intron	N/A	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.2044-5_2044-4insT		splice_region intron	N/A	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.2011-5_2011-4insT		splice_region intron	N/A	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.000311 AC: 47 AN: 151114 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 231 AN: 228492 AF XY: 0.00130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.000215

Gnomad EAS exome AF: 0.000538

Gnomad FIN exome AF: 0.000207

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.000540

GnomAD4 exome AF: 0.000631 AC: 902 AN: 1429078 Hom.: 6 Cov.: 31 AF XY: 0.000756 AC XY: 538 AN XY: 711340

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

African (AFR) AF: 0.000428 AC: 14 AN: 32704

American (AMR) AF: 0.000182 AC: 8 AN: 43998

Ashkenazi Jewish (ASJ) AF: 0.0000785 AC: 2 AN: 25468

East Asian (EAS) AF: 0.000389 AC: 15 AN: 38562

South Asian (SAS) AF: 0.00548 AC: 466 AN: 85054

European-Finnish (FIN) AF: 0.000154 AC: 8 AN: 51936

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5630

European-Non Finnish (NFE) AF: 0.000324 AC: 352 AN: 1086722

Other (OTH) AF: 0.000593 AC: 35 AN: 59004

⚠️ 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: 0.000311 AC: 47 AN: 151226 Hom.: 1 Cov.: 33 AF XY: 0.000271 AC XY: 20 AN XY: 73892

African (AFR) AF: 0.000218 AC: 9 AN: 41250

American (AMR) AF: 0.000198 AC: 3 AN: 15164

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

East Asian (EAS) AF: 0.000777 AC: 4 AN: 5148

South Asian (SAS) AF: 0.00417 AC: 20 AN: 4792

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

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67734

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

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.000200

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.28
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: rs549232924; hg19: chr2-166898938;