12-51745885-CTTT-CT

Variant names:

• chr12-51745885-CTT-C
• rs769940455
• NM_001330260.2:c.1999-6_1999-5delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001330260.2(SCN8A):​c.1999-6_1999-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000877 in 1,210,482 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: SCN8A NM_001330260.2 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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, STRONG Submitted by: ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 13

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1999-6_1999-5delTT		splice_region intron	N/A	NP_001317189.1	Q9UQD0-2
	SCN8A	NM_014191.4	MANE Plus Clinical	c.1999-6_1999-5delTT		splice_region intron	N/A	NP_055006.1	Q9UQD0-1
	SCN8A	NM_001177984.3		c.1999-6_1999-5delTT		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.1999-17_1999-16delTT		intron	N/A	ENSP00000346534.4	Q9UQD0-1
	SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.1999-17_1999-16delTT		intron	N/A	ENSP00000487583.2	Q9UQD0-2
	SCN8A	ENST00000599343.5	TSL:5	c.2032-17_2032-16delTT		intron	N/A	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes AF: 0.0000490 AC: 7 AN: 142794 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000256

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: 0.000340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000464

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00462 AC: 370 AN: 80108 AF XY: 0.00472

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.00504

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00615

GnomAD4 exome AF: 0.000988 AC: 1055 AN: 1067688 Hom.: 0 AF XY: 0.00113 AC XY: 598 AN XY: 530256

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

African (AFR) AF: 0.000971 AC: 23 AN: 23676

American (AMR) AF: 0.00310 AC: 75 AN: 24158

Ashkenazi Jewish (ASJ) AF: 0.00178 AC: 32 AN: 17984

East Asian (EAS) AF: 0.00144 AC: 45 AN: 31302

South Asian (SAS) AF: 0.00295 AC: 173 AN: 58740

European-Finnish (FIN) AF: 0.00128 AC: 49 AN: 38162

Middle Eastern (MID) AF: 0.000443 AC: 2 AN: 4516

European-Non Finnish (NFE) AF: 0.000741 AC: 611 AN: 824826

Other (OTH) AF: 0.00102 AC: 45 AN: 44324

⚠️ 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: 0.0000490 AC: 7 AN: 142794 Hom.: 0 Cov.: 31 AF XY: 0.0000721 AC XY: 5 AN XY: 69382

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

African (AFR) AF: 0.0000256 AC: 1 AN: 39078

American (AMR) AF: 0.00 AC: 0 AN: 14338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4982

South Asian (SAS) AF: 0.00 AC: 0 AN: 4476

European-Finnish (FIN) AF: 0.000340 AC: 3 AN: 8818

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

European-Non Finnish (NFE) AF: 0.0000464 AC: 3 AN: 64674

Other (OTH) AF: 0.00 AC: 0 AN: 1938

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000698 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;