Genetic Variant SCN9A:p.Val1309Ile (chr2-166228972-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM5PP3

The NM_001365536.1(SCN9A):c.3925G>A(p.Val1309Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,453,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1309F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense, splice_region

Scores

Splicing: ADA: 0.9994

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

16 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001365536.1

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-166228972-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6358.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.3925G>A	p.Val1309Ile	missense splice_region	Exon 22 of 27	NP_001352465.1
SCN9A	NM_002977.4		c.3892G>A	p.Val1298Ile	missense splice_region	Exon 22 of 27	NP_002968.2
SCN1A-AS1	NR_110260.1		n.612-19223C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN9A	ENST00000642356.2	MANE Select	c.3925G>A	p.Val1309Ile	missense splice_region	Exon 22 of 27	ENSP00000495601.1
SCN9A	ENST00000303354.11	TSL:5	c.3925G>A	p.Val1309Ile	missense splice_region	Exon 22 of 27	ENSP00000304748.7
SCN9A	ENST00000409672.5	TSL:5	c.3892G>A	p.Val1298Ile	missense splice_region	Exon 22 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1453624

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

722186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33252

American (AMR)

AF:

0.00

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

85308

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00000542

AC:

AN:

1106050

Other (OTH)

AF:

0.00

AC:

AN:

60040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

PhyloP100

7.9

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.92

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Benign

0.17

Vest4

0.69

MutPred

0.72

Gain of catalytic residue at L1303 (P = 0.0314)

MVP

0.80

MPC

0.51

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.79

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over