rs587780452

Variant names:

• chr12-51751340-TCTTA-T
• rs587780452
• NM_001330260.2:c.2132-8_2132-5delTACT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001330260.2(SCN8A):​c.2132-8_2132-5delTACT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000558 in 1,434,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). The gene SCN8A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: SCN8A NM_001330260.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.19
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 13

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• cognitive impairment with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 5

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile convulsions and choreoathetosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonus, familial, 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for SCN8A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 12-51751340-TCTTA-T is Benign according to our data. Variant chr12-51751340-TCTTA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 130243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330260.2. 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
	SCN8A	NM_001330260.2	MANE Select	c.2132-8_2132-5delTACT		splice_region intron	N/A	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.2132-8_2132-5delTACT		splice_region intron	N/A	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.2132-8_2132-5delTACT		splice_region intron	N/A	NP_001171455.1	Q9UQD0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.2132-14_2132-11delCTTA		intron	N/A	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.2132-14_2132-11delCTTA		intron	N/A	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.2165-14_2165-11delCTTA		intron	N/A	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000822 AC: 2 AN: 243182 AF XY: 0.00000759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000558 AC: 8 AN: 1434338 Hom.: 0 AF XY: 0.00000700 AC XY: 5 AN XY: 713906

African (AFR) AF: 0.0000304 AC: 1 AN: 32862

American (AMR) AF: 0.00 AC: 0 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 84578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000642 AC: 7 AN: 1089778

Other (OTH) AF: 0.00 AC: 0 AN: 59328

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Early-infantile DEE (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587780452;

hg19: chr12-52145124;