12-51745885-CTTT-CT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_014191.4(SCN8A):c.1999-6_1999-5del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,210,482 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: SCN8A NM_014191.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.316

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000988 (1055/1067688) while in subpopulation AMR AF= 0.0031 (75/24158). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4_exome. There are 598 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN8A	NM_001330260.2	c.1999-6_1999-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000627620.5
SCN8A	NM_014191.4	c.1999-6_1999-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000354534.11
SCN8A	NM_001177984.3	c.1999-6_1999-5del		splice_polypyrimidine_tract_variant, intron_variant
SCN8A	NM_001369788.1	c.1999-6_1999-5del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN8A	ENST00000354534.11	c.1999-6_1999-5del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014191.4	P4
SCN8A	ENST00000627620.5	c.1999-6_1999-5del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330260.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000490 AC: 7 AN: 142794 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000256

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: 0.000340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00462 AC: 370 AN: 80108 Hom.: 0 AF XY: 0.00472 AC XY: 202 AN XY: 42762

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00504

Gnomad SAS exome AF: 0.00598

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00615

GnomAD4 exome AF: 0.000988 AC: 1055 AN: 1067688 Hom.: 0 AF XY: 0.00113 AC XY: 598 AN XY: 530256

Gnomad4 AFR exome AF: 0.000971

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00178

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.00295

Gnomad4 FIN exome AF: 0.00128

Gnomad4 NFE exome AF: 0.000741

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.0000490 AC: 7 AN: 142794 Hom.: 0 Cov.: 31 AF XY: 0.0000721 AC XY: 5 AN XY: 69382

Gnomad4 AFR AF: 0.0000256

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000340

Gnomad4 NFE AF: 0.0000464

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000698 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs769940455; hg19: chr12-52139669;