12-51745885-CTTT-CTTTTTT

Variant names:

• chr12-51745885-C-CTTT
• rs769940455
• NM_001330260.2:c.1999-7_1999-5dupTTT

Variant summary

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

The NM_001330260.2(SCN8A):​c.1999-7_1999-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,084,144 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (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 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1999-7_1999-5dupTTT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1999-7_1999-5dupTTT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1999-7_1999-5dupTTT		splice_region_variant, intron_variant	Intron 12 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.1999-7_1999-5dupTTT		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_1999-17insTTT		intron_variant	Intron 12 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1999-18_1999-17insTTT		intron_variant	Intron 12 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.2032-18_2032-17insTTT		intron_variant	Intron 11 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1999-18_1999-17insTTT		intron_variant	Intron 11 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000374 AC: 3 AN: 80108 AF XY: 0.0000468

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: 0.0000522

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 18 AN: 1084144 Hom.: 0 Cov.: 0 AF XY: 0.0000223 AC XY: 12 AN XY: 538534

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

African (AFR) AF: 0.00 AC: 0 AN: 24096

American (AMR) AF: 0.0000404 AC: 1 AN: 24730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18282

East Asian (EAS) AF: 0.00 AC: 0 AN: 31738

South Asian (SAS) AF: 0.000117 AC: 7 AN: 60020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4564

European-Non Finnish (NFE) AF: 0.00000956 AC: 8 AN: 836944

Other (OTH) AF: 0.0000444 AC: 2 AN: 45012

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs769940455; hg19: chr12-52139669;