rs771414635

Variant names:

• chr12-51807435-A-T
• rs771414635
• NM_001330260.2:c.*6A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_001330260.2(SCN8A):​c.*6A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,449,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN8A NM_001330260.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.335
• 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.*6A>T		3_prime_UTR_variant	Exon 27 of 27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.*6A>T		3_prime_UTR_variant	Exon 27 of 27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.*6A>T		3_prime_UTR_variant	Exon 26 of 26		NP_001171455.1
SCN8A	NM_001369788.1	c.*6A>T		3_prime_UTR_variant	Exon 26 of 26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.*6A>T		3_prime_UTR_variant	Exon 27 of 27	1	NM_014191.4	ENSP00000346534.4
SCN8A	ENST00000627620.5	c.*6A>T		3_prime_UTR_variant	Exon 27 of 27	5	NM_001330260.2	ENSP00000487583.2
SCN8A	ENST00000599343.5	c.*6A>T		downstream_gene_variant		5		ENSP00000476447.3
SCN8A	ENST00000355133.7	c.*6A>T		downstream_gene_variant		1		ENSP00000347255.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 224228 AF XY: 0.00000820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000629

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: 0.000177

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449896 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720142

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.0000468 AC: 2 AN: 42776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 84630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105842

Other (OTH) AF: 0.0000333 AC: 2 AN: 59992

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.4
DANN	Benign	0.80
PhyloP100		0.34

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: rs771414635; hg19: chr12-52201219;