12-51745899-A-T

Position:

• chr12-51745899-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001330260.2(SCN8A):​c.1999-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,245,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCN8A NM_001330260.2 splice_region, intron
• Scores: Splicing: ADA: 0.00005228
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.599

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-51745899-A-T is Benign according to our data. Variant chr12-51745899-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 461335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51745899-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00145 (1800/1245576) while in subpopulation SAS AF= 0.00414 (249/60156). AF 95% confidence interval is 0.00372. There are 0 homozygotes in gnomad4_exome. There are 1017 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 1800 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1999-4A>T		splice_region_variant, intron_variant		ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1999-4A>T		splice_region_variant, intron_variant		ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1999-4A>T		splice_region_variant, intron_variant			NP_001171455.1
SCN8A	NM_001369788.1	c.1999-4A>T		splice_region_variant, intron_variant			NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1999-4A>T		splice_region_variant, intron_variant		1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1999-4A>T		splice_region_variant, intron_variant		5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.2032-4A>T		splice_region_variant, intron_variant		5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1999-4A>T		splice_region_variant, intron_variant		1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 6 AN: 149700 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000245

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: 0.000410

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00249 AC: 400 AN: 160576 Hom.: 0 AF XY: 0.00239 AC XY: 209 AN XY: 87470

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.00213

Gnomad EAS exome AF: 0.00321

Gnomad SAS exome AF: 0.00373

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00405

GnomAD4 exome AF: 0.00145 AC: 1800 AN: 1245576 Hom.: 0 Cov.: 33 AF XY: 0.00166 AC XY: 1017 AN XY: 612660

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.00228

Gnomad4 EAS exome AF: 0.00217

Gnomad4 SAS exome AF: 0.00414

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000401 AC: 6 AN: 149700 Hom.: 0 Cov.: 31 AF XY: 0.0000412 AC XY: 3 AN XY: 72876

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000410

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 06, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.23
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.0080
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: rs765240974; hg19: chr12-52139683; COSMIC: COSV61984792; COSMIC: COSV61984792;