12-51745885-CTTT-CTTTT

Variant names:

• chr12-51745885-C-CT
• rs769940455
• NM_001330260.2:c.1999-5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001330260.2(SCN8A):​c.1999-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0709 in 1,061,912 control chromosomes in the GnomAD database, including 2 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.082 (2 hom.)
• Consequence: SCN8A NM_001330260.2 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.316
• 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 Submitted by: ClinGen
• developmental and epileptic encephalopathy, 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-51745885-C-CT is Benign according to our data. Variant chr12-51745885-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1294100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00233 (333/142822) while in subpopulation SAS AF = 0.00471 (21/4458). AF 95% confidence interval is 0.00316. There are 0 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 333 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1999-5dupT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1999-5dupT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1999-5dupT		splice_region_variant, intron_variant	Intron 12 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.1999-5dupT		splice_region_variant, intron_variant	Intron 12 of 25		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1999-18_1999-17insT		intron_variant	Intron 12 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1999-18_1999-17insT		intron_variant	Intron 12 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.2032-18_2032-17insT		intron_variant	Intron 11 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1999-18_1999-17insT		intron_variant	Intron 11 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 329 AN: 142782 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.000907

Gnomad EAS AF: 0.000803

Gnomad SAS AF: 0.00469

Gnomad FIN AF: 0.00352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00292

Gnomad OTH AF: 0.000516

GnomAD2 exomes AF: 0.0969 AC: 7760 AN: 80108 AF XY: 0.0980

Gnomad AFR exome AF: 0.0967

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0855

Gnomad NFE exome AF: 0.0853

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0815 AC: 74942 AN: 919090 Hom.: 2 Cov.: 0 AF XY: 0.0813 AC XY: 37293 AN XY: 458990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0813 AC: 1672 AN: 20558

American (AMR) AF: 0.0805 AC: 1840 AN: 22852

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 1376 AN: 15896

East Asian (EAS) AF: 0.0784 AC: 2138 AN: 27260

South Asian (SAS) AF: 0.100 AC: 5506 AN: 54936

European-Finnish (FIN) AF: 0.0715 AC: 2495 AN: 34880

Middle Eastern (MID) AF: 0.0514 AC: 209 AN: 4066

European-Non Finnish (NFE) AF: 0.0808 AC: 56557 AN: 700280

Other (OTH) AF: 0.0821 AC: 3149 AN: 38362

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00233 AC: 333 AN: 142822 Hom.: 0 Cov.: 31 AF XY: 0.00245 AC XY: 170 AN XY: 69418

African (AFR) AF: 0.00156 AC: 61 AN: 39160

American (AMR) AF: 0.00160 AC: 23 AN: 14354

Ashkenazi Jewish (ASJ) AF: 0.000907 AC: 3 AN: 3308

East Asian (EAS) AF: 0.000805 AC: 4 AN: 4966

South Asian (SAS) AF: 0.00471 AC: 21 AN: 4458

European-Finnish (FIN) AF: 0.00352 AC: 31 AN: 8812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.00292 AC: 189 AN: 64652

Other (OTH) AF: 0.000512 AC: 1 AN: 1954

Alfa AF: 0.00508 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs769940455; hg19: chr12-52139669; COSMIC: COSV105910300; COSMIC: COSV105910300;