Genetic Variant SCN9A:p.Ile1225Ile (chr2-166238220-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001365536.1(SCN9A):c.3675C>A(p.Ile1225Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,600,150 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 48 hom. )

Consequence

SCN9A
NM_001365536.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.750

Publications

3 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 2-166238220-G-T is Benign according to our data. Variant chr2-166238220-G-T is described in ClinVar as Benign. ClinVar VariationId is 130264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.75 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00207 (315/152046) while in subpopulation EAS AF = 0.0505 (261/5164). AF 95% confidence interval is 0.0455. There are 4 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,SD 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	UniProt
SCN9A	NM_001365536.1	MANE Select	c.3675C>A	p.Ile1225Ile	synonymous	Exon 20 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.3642C>A	p.Ile1214Ile	synonymous	Exon 20 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.612-9975G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.3675C>A	p.Ile1225Ile	synonymous	Exon 20 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.3675C>A	p.Ile1225Ile	synonymous	Exon 20 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.3642C>A	p.Ile1214Ile	synonymous	Exon 20 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

316

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0508

Gnomad SAS

AF:

0.00457

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00426

AC:

996

AN:

233756

AF XY:

0.00413

show subpopulations

Gnomad AFR exome

AF:

0.000341

Gnomad AMR exome

AF:

0.0000941

Gnomad ASJ exome

AF:

0.000514

Gnomad EAS exome

AF:

0.0501

Gnomad FIN exome

AF:

0.000898

Gnomad NFE exome

AF:

0.000312

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00148

AC:

2144

AN:

1448104

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1064

AN XY:

719562

show subpopulations

African (AFR)

AF:

0.000181

AC:

AN:

33122

American (AMR)

AF:

0.0000928

AC:

AN:

43100

Ashkenazi Jewish (ASJ)

AF:

0.000425

AC:

AN:

25910

East Asian (EAS)

AF:

0.0406

AC:

1598

AN:

39312

South Asian (SAS)

AF:

0.00179

AC:

149

AN:

83132

European-Finnish (FIN)

AF:

0.000829

AC:

AN:

53098

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000102

AC:

113

AN:

1104774

Other (OTH)

AF:

0.00359

AC:

215

AN:

59904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00207

AC:

315

AN:

152046

Hom.:

Cov.:

AF XY:

0.00235

AC XY:

175

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41464

American (AMR)

AF:

0.000131

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0505

AC:

261

AN:

5164

South Asian (SAS)

AF:

0.00499

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67974

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000267

Hom.:

Bravo

AF:

0.00244

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

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)

not provided (1)

Paroxysmal extreme pain disorder (1)

Primary erythromelalgia (1)

Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.7

(source)

DANN

Benign

0.75

PhyloP100

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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