rs765240974

Positions:

• chr12-51745899-A-G
• chr12-51745899-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014191.4(SCN8A):​c.1999-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000952 in 1,261,076 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000095 (0 hom.)
• Consequence: SCN8A NM_014191.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006585
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-51745899-A-G is Benign according to our data. Variant chr12-51745899-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1091429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1999-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1999-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1999-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001171455.1
SCN8A	NM_001369788.1	c.1999-4A>G		splice_region_variant, splice_polypyrimidine_tract_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>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.1999-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000952 AC: 12 AN: 1261076 Hom.: 0 Cov.: 33 AF XY: 0.00000806 AC XY: 5 AN XY: 620466

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

Oct 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.81
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
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;