rs758276968

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_001330260.2(SCN8A):c.1855_1863delGGCTACAGC(p.Gly619_Ser621del) variant causes a conservative 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_001330260.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 6.66

Publications

1 publications found

Variant links:

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

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001330260.2.

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 VariationId is 406253.

BS2

High AC in GnomAd4 at 17 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN8A	NM_001330260.2	MANE Select	c.1855_1863delGGCTACAGC	p.Gly619_Ser621del	conservative_inframe_deletion	Exon 12 of 27	NP_001317189.1	Q9UQD0-2
SCN8A	NM_014191.4	MANE Plus Clinical	c.1855_1863delGGCTACAGC	p.Gly619_Ser621del	conservative_inframe_deletion	Exon 12 of 27	NP_055006.1	Q9UQD0-1
SCN8A	NM_001177984.3		c.1855_1863delGGCTACAGC	p.Gly619_Ser621del	conservative_inframe_deletion	Exon 12 of 26	NP_001171455.1	Q9UQD0-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.1855_1863delGGCTACAGC	p.Gly619_Ser621del	conservative_inframe_deletion	Exon 12 of 27	ENSP00000346534.4	Q9UQD0-1
SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.1855_1863delGGCTACAGC	p.Gly619_Ser621del	conservative_inframe_deletion	Exon 12 of 27	ENSP00000487583.2	Q9UQD0-2
SCN8A	ENST00000599343.5	TSL:5	c.1855_1863delGGCTACAGC	p.Gly619_Ser621del	conservative_inframe_deletion	Exon 11 of 26	ENSP00000476447.3	Q9UQD0-3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000125

AC:

AN:

231440

AF XY:

0.000142

show subpopulations

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 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.:

AF XY:

0.0000938

AC XY:

AN XY:

724572

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33402

American (AMR)

AF:

0.000160

AC:

AN:

43730

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.0000759

AC:

AN:

39516

South Asian (SAS)

AF:

0.000198

AC:

AN:

85836

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000937

AC:

104

AN:

1109928

Other (OTH)

AF:

0.0000666

AC:

AN:

60100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41574

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000125

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.7

Mutation Taster

=19/181

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over