2-166046984-CAAA-CA

Variant names:

• chr2-166046984-CAA-C
• rs372840031
• NM_001165963.4:c.1171-10_1171-9delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001165963.4(SCN1A):​c.1171-10_1171-9delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,612,376 control chromosomes in the GnomAD database, including 1,340 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (72 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1268 hom.)
• Consequence: SCN1A NM_001165963.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.89
• 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 -16 ACMG points.

• BP6: Variant 2-166046984-CAA-C is Benign according to our data. Variant chr2-166046984-CAA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0286 (4347/152212) while in subpopulation NFE AF = 0.0424 (2885/68014). AF 95% confidence interval is 0.0411. There are 72 homozygotes in GnomAd4. There are 2081 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4347 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.1171-10_1171-9delTT		intron	N/A	NP_001159435.1	P35498-1
	SCN1A	NM_001202435.3		c.1171-10_1171-9delTT		intron	N/A	NP_001189364.1	P35498-1
	SCN1A	NM_001353948.2		c.1171-10_1171-9delTT		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.1171-10_1171-9delTT		intron	N/A	ENSP00000501589.1	P35498-1
	SCN1A	ENST00000303395.9	TSL:5	c.1171-10_1171-9delTT		intron	N/A	ENSP00000303540.4	P35498-1
	SCN1A	ENST00000375405.7	TSL:5	c.1171-10_1171-9delTT		intron	N/A	ENSP00000364554.3	P35498-2

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4349 AN: 152094 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.00850

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0349

GnomAD2 exomes AF: 0.0280 AC: 6990 AN: 249920 AF XY: 0.0277

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0392 AC: 57286 AN: 1460164 Hom.: 1268 AF XY: 0.0380 AC XY: 27579 AN XY: 726536

African (AFR) AF: 0.00577 AC: 193 AN: 33434

American (AMR) AF: 0.0216 AC: 965 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 590 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00449 AC: 387 AN: 86230

European-Finnish (FIN) AF: 0.0396 AC: 2116 AN: 53390

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5760

European-Non Finnish (NFE) AF: 0.0459 AC: 50992 AN: 1110540

Other (OTH) AF: 0.0327 AC: 1975 AN: 60322

GnomAD4 genome AF: 0.0286 AC: 4347 AN: 152212 Hom.: 72 Cov.: 32 AF XY: 0.0280 AC XY: 2081 AN XY: 74416

African (AFR) AF: 0.00848 AC: 352 AN: 41532

American (AMR) AF: 0.0285 AC: 436 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

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

South Asian (SAS) AF: 0.00478 AC: 23 AN: 4816

European-Finnish (FIN) AF: 0.0441 AC: 467 AN: 10592

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0424 AC: 2885 AN: 68014

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0313 Hom.: 14

Bravo AF: 0.0274

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Epilepsy (1)
-	-	1	Familial hemiplegic migraine (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs372840031; hg19: chr2-166903494;