chr12-51721747-AGCTACAGCG-A

Position:

• chr12-51721747-AGCTACAGCG-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_014191.4(SCN8A):​c.1855_1863del​(p.Gly619_Ser621del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000957 in 1,609,250 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: SCN8A NM_014191.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 6.66

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_014191.4.
• BP6: Variant 12-51721747-AGCTACAGCG-A is Benign according to our data. Variant chr12-51721747-AGCTACAGCG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406253.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.1855_1863del	p.Gly619_Ser621del	inframe_deletion	12/27	ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.1855_1863del	p.Gly619_Ser621del	inframe_deletion	12/27	ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.1855_1863del	p.Gly619_Ser621del	inframe_deletion	12/26		NP_001171455.1
SCN8A	NM_001369788.1	c.1855_1863del	p.Gly619_Ser621del	inframe_deletion	12/26		NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.1855_1863del	p.Gly619_Ser621del	inframe_deletion	12/27	1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.1855_1863del	p.Gly619_Ser621del	inframe_deletion	12/27	5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 29 AN: 231440 Hom.: 0 AF XY: 0.000142 AC XY: 18 AN XY: 127138

Gnomad AFR exome AF: 0.0000750

Gnomad AMR exome AF: 0.000151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad SAS exome AF: 0.000266

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000940 AC: 137 AN: 1456936 Hom.: 0 AF XY: 0.0000938 AC XY: 68 AN XY: 724572

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000937

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74474

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN8A: PM4, BS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs758276968; hg19: chr12-52115531;