rs144424662

Variant names:

• chr12-51786754-A-C
• rs144424662
• NM_001330260.2:c.4155A>C
• SCN8A p.Thr1385Thr

Your query was ambiguous. Multiple possible variants found:

• chr12-51786754-A-C
• chr12-51786754-A-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001330260.2(SCN8A):​c.4155A>C​(p.Thr1385Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SCN8A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: SCN8A NM_001330260.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.932
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-51786754-A-C is Benign according to our data. Variant chr12-51786754-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285485.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000453 (69/152388) while in subpopulation AFR AF = 0.00161 (67/41598). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4155A>C	p.Thr1385Thr	synonymous	Exon 22 of 27	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.4155A>C	p.Thr1385Thr	synonymous	Exon 22 of 27	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.4032A>C	p.Thr1344Thr	synonymous	Exon 21 of 26	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.4155A>C	p.Thr1385Thr	synonymous	Exon 22 of 27	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.4155A>C	p.Thr1385Thr	synonymous	Exon 22 of 27	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.4188A>C	p.Thr1396Thr	synonymous	Exon 21 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152270 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 248966 AF XY: 0.000104

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461650 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727104

African (AFR) AF: 0.00131 AC: 44 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111848

Other (OTH) AF: 0.0000663 AC: 4 AN: 60372

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152388 Hom.: 0 Cov.: 32 AF XY: 0.000496 AC XY: 37 AN XY: 74526

African (AFR) AF: 0.00161 AC: 67 AN: 41598

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.000487

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Early-infantile DEE (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.6
DANN	Benign	0.65
PhyloP100		-0.93

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: rs144424662;

hg19: chr12-52180538;