12-51745885-CTTT-CTTTTT

Variant names:

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

Variant summary

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

The NM_001330260.2(SCN8A):​c.1999-6_1999-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00035 (0 hom.)
  • Failed GnomAD Quality Control
• 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.1999-6_1999-5dupTT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1999-6_1999-5dupTT		splice_region_variant, intron_variant	Intron 12 of 26	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1999-6_1999-5dupTT		splice_region_variant, intron_variant	Intron 12 of 25		NP_001171455.1
SCN8A	NM_001369788.1	c.1999-6_1999-5dupTT		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_1999-17insTT		intron_variant	Intron 12 of 26	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.1999-18_1999-17insTT		intron_variant	Intron 12 of 26	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.2032-18_2032-17insTT		intron_variant	Intron 11 of 25	5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.1999-18_1999-17insTT		intron_variant	Intron 11 of 24	1		ENSP00000347255.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 142890 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00131 AC: 105 AN: 80108 AF XY: 0.00140

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00167

Gnomad ASJ exome AF: 0.000660

Gnomad EAS exome AF: 0.00244

Gnomad FIN exome AF: 0.000568

Gnomad NFE exome AF: 0.000992

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.000352 AC: 380 AN: 1080142 Hom.: 0 Cov.: 0 AF XY: 0.000393 AC XY: 211 AN XY: 536554

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

African (AFR) AF: 0.000458 AC: 11 AN: 23994

American (AMR) AF: 0.000609 AC: 15 AN: 24614

Ashkenazi Jewish (ASJ) AF: 0.000549 AC: 10 AN: 18204

East Asian (EAS) AF: 0.000569 AC: 18 AN: 31622

South Asian (SAS) AF: 0.00132 AC: 79 AN: 59650

European-Finnish (FIN) AF: 0.000311 AC: 12 AN: 38624

Middle Eastern (MID) AF: 0.000440 AC: 2 AN: 4550

European-Non Finnish (NFE) AF: 0.000254 AC: 212 AN: 834024

Other (OTH) AF: 0.000468 AC: 21 AN: 44860

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 142930 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 69486

African (AFR) AF: 0.00 AC: 0 AN: 39170

American (AMR) AF: 0.00 AC: 0 AN: 14370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3312

East Asian (EAS) AF: 0.00 AC: 0 AN: 4968

South Asian (SAS) AF: 0.00 AC: 0 AN: 4458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8838

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64702

Other (OTH) AF: 0.00 AC: 0 AN: 1954

Alfa AF: 0.000399 Hom.: 2

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;