rs202084411

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001365536.1(SCN9A):c.4645T>C(p.Trp1549Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00239 in 1,612,768 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1549Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 13 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.17

Publications

30 publications found

Variant links:

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN9A links:

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015026212).

BP6

Variant 2-166204084-A-G is Benign according to our data. Variant chr2-166204084-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 234412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN9A	NM_001365536.1	MANE Select	c.4645T>C	p.Trp1549Arg	missense	Exon 26 of 27	NP_001352465.1
SCN9A	NM_002977.4		c.4612T>C	p.Trp1538Arg	missense	Exon 26 of 27	NP_002968.2
SCN1A-AS1	NR_110260.1		n.611+4266A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN9A	ENST00000642356.2	MANE Select	c.4645T>C	p.Trp1549Arg	missense	Exon 26 of 27	ENSP00000495601.1
SCN9A	ENST00000303354.11	TSL:5	c.4645T>C	p.Trp1549Arg	missense	Exon 26 of 27	ENSP00000304748.7
SCN9A	ENST00000409672.5	TSL:5	c.4612T>C	p.Trp1538Arg	missense	Exon 26 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

288

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00314

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00205

AC:

509

AN:

248200

AF XY:

0.00236

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.0000553

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00244

AC:

3559

AN:

1460646

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

1921

AN XY:

726628

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33454

American (AMR)

AF:

0.00155

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26100

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39592

South Asian (SAS)

AF:

0.00571

AC:

492

AN:

86216

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00261

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00250

AC:

2777

AN:

1111262

Other (OTH)

AF:

0.00244

AC:

147

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

182

365

547

730

912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.00189

AC:

288

AN:

152122

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41568

American (AMR)

AF:

0.00105

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00539

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00314

AC:

213

AN:

67870

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00225

Hom.:

Bravo

AF:

0.00162

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00334

AC:

ExAC

AF:

0.00207

AC:

250

Asia WGS

AF:

0.00173

AC:

AN:

3474

EpiCase

AF:

0.00295

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)

Inborn genetic diseases (1)

Paroxysmal extreme pain disorder (1)

Primary erythromelalgia (1)

SCN9A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Uncertain

0.72

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

0.81

PhyloP100

4.2

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.63

Sift

Benign

0.92

Sift4G

Benign

0.36

Vest4

0.82

MutPred

0.65

Loss of catalytic residue at L1536 (P = 0.0064)

MVP

0.72

MPC

0.24

ClinPred

0.022

GERP RS

4.5

Varity_R

0.60

gMVP

0.72

Mutation Taster

=3/97

disease causing

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over