rs148027656

Positions:

• chr12-51699800-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001330260.2(SCN8A):​c.928+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000687 in 1,600,740 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: SCN8A NM_001330260.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.432

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]

SCN8A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-51699800-C-T is Benign according to our data. Variant chr12-51699800-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 139068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51699800-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00367 (558/152208) while in subpopulation AFR AF= 0.0127 (528/41504). AF 95% confidence interval is 0.0118. There are 2 homozygotes in gnomad4. There are 274 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 558 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.928+9C>T		intron_variant		ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.928+9C>T		intron_variant		ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.928+9C>T		intron_variant			NP_001171455.1
SCN8A	NM_001369788.1	c.928+9C>T		intron_variant			NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.928+9C>T		intron_variant		1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.928+9C>T		intron_variant		5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.928+9C>T		intron_variant		5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.928+9C>T		intron_variant		1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152090 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000916 AC: 216 AN: 235824 Hom.: 4 AF XY: 0.000690 AC XY: 88 AN XY: 127582

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000606

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.000864

GnomAD4 exome AF: 0.000373 AC: 541 AN: 1448532 Hom.: 3 Cov.: 28 AF XY: 0.000291 AC XY: 210 AN XY: 720530

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.000847

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000907

Gnomad4 OTH exome AF: 0.000967

GnomAD4 genome AF: 0.00367 AC: 558 AN: 152208 Hom.: 2 Cov.: 31 AF XY: 0.00368 AC XY: 274 AN XY: 74440

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00260 Hom.: 0

Bravo AF: 0.00447

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 23, 2016	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs148027656; hg19: chr12-52093584;