dbSNP rs60637: SCN8A:p.Pro1824Pro (chr12-51806958-C-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014191.4(SCN8A):c.5472C>A(p.Pro1824Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,622 control chromosomes in the GnomAD database, including 406,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1824P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.60 ( 30605 hom., cov: 32)

Exomes 𝑓: 0.71 ( 376227 hom. )

Consequence

SCN8A
NM_014191.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: -0.0570

Publications

25 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 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

SCN8A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 12-51806958-C-A is Benign according to our data. Variant chr12-51806958-C-A is described in ClinVar as Benign. ClinVar VariationId is 130251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.057 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014191.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN8A	NM_001330260.2	MANE Select	c.5472C>A	p.Pro1824Pro	synonymous	Exon 27 of 27	NP_001317189.1
SCN8A	NM_014191.4	MANE Plus Clinical	c.5472C>A	p.Pro1824Pro	synonymous	Exon 27 of 27	NP_055006.1
SCN8A	NM_001177984.3		c.5349C>A	p.Pro1783Pro	synonymous	Exon 26 of 26	NP_001171455.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN8A	ENST00000354534.11	TSL:1 MANE Plus Clinical	c.5472C>A	p.Pro1824Pro	synonymous	Exon 27 of 27	ENSP00000346534.4
SCN8A	ENST00000627620.5	TSL:5 MANE Select	c.5472C>A	p.Pro1824Pro	synonymous	Exon 27 of 27	ENSP00000487583.2
SCN8A	ENST00000599343.5	TSL:5	c.5505C>A	p.Pro1835Pro	synonymous	Exon 26 of 26	ENSP00000476447.3

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91608

AN:

151874

Hom.:

30597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.816

Gnomad AMR

AF:

0.707

Gnomad ASJ

AF:

0.657

Gnomad EAS

AF:

0.573

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.705

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.756

Gnomad OTH

AF:

0.654

GnomAD2 exomes

AF:

0.654

AC:

163303

AN:

249530

AF XY:

0.647

show subpopulations

Gnomad AFR exome

AF:

0.295

Gnomad AMR exome

AF:

0.746

Gnomad ASJ exome

AF:

0.678

Gnomad EAS exome

AF:

0.574

Gnomad FIN exome

AF:

0.720

Gnomad NFE exome

AF:

0.751

Gnomad OTH exome

AF:

0.686

GnomAD4 exome

AF:

0.707

AC:

1033975

AN:

1461630

Hom.:

376227

Cov.:

AF XY:

0.699

AC XY:

507872

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.291

AC:

9744

AN:

33480

American (AMR)

AF:

0.743

AC:

33235

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.678

AC:

17725

AN:

26132

East Asian (EAS)

AF:

0.529

AC:

20990

AN:

39698

South Asian (SAS)

AF:

0.370

AC:

31910

AN:

86254

European-Finnish (FIN)

AF:

0.733

AC:

39134

AN:

53394

Middle Eastern (MID)

AF:

0.619

AC:

3568

AN:

5768

European-Non Finnish (NFE)

AF:

0.752

AC:

836321

AN:

1111808

Other (OTH)

AF:

0.685

AC:

41348

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

18637

37275

55912

74550

93187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19972

39944

59916

79888

99860

<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:

0.603

AC:

91631

AN:

151992

Hom.:

30605

Cov.:

AF XY:

0.598

AC XY:

44391

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.308

AC:

12746

AN:

41446

American (AMR)

AF:

0.707

AC:

10807

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

2277

AN:

3468

East Asian (EAS)

AF:

0.572

AC:

2948

AN:

5150

South Asian (SAS)

AF:

0.367

AC:

1767

AN:

4820

European-Finnish (FIN)

AF:

0.705

AC:

7420

AN:

10520

Middle Eastern (MID)

AF:

0.609

AC:

179

AN:

294

European-Non Finnish (NFE)

AF:

0.756

AC:

51376

AN:

67994

Other (OTH)

AF:

0.649

AC:

1370

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1615

3231

4846

6462

8077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

730

1460

2190

2920

3650

<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:

0.692

Hom.:

65315

Bravo

AF:

0.598

Asia WGS

AF:

0.439

AC:

1526

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Cognitive impairment with or without cerebellar ataxia (1)

Developmental and epileptic encephalopathy (1)

Developmental and epileptic encephalopathy, 13 (1)

Inborn genetic diseases (1)

Myoclonus, familial, 2 (1)

Seizures, benign familial infantile, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

6.4

(source)

DANN

Benign

0.85

PhyloP100

-0.057

Mutation Taster

=71/29

polymorphism

(source)

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

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