Genetic Variant SCN9A:p.Asp974Glu (chr2-166272828-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001365536.1(SCN9A):c.2922C>G(p.Asp974Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,364,406 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.07

Publications

1 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.2922C>G	p.Asp974Glu	missense	Exon 17 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.2889C>G	p.Asp963Glu	missense	Exon 17 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.870-4260G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.2922C>G	p.Asp974Glu	missense	Exon 17 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.2922C>G	p.Asp974Glu	missense	Exon 17 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.2889C>G	p.Asp963Glu	missense	Exon 17 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000116

AC:

AN:

172670

AF XY:

0.0000220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1364406

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

668552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30214

American (AMR)

AF:

0.00

AC:

AN:

28888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19902

East Asian (EAS)

AF:

0.00

AC:

AN:

38934

South Asian (SAS)

AF:

0.0000298

AC:

AN:

67096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1068178

Other (OTH)

AF:

0.00

AC:

AN:

56162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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.:

ExAC

AF:

0.00000868

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.63

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.6

PhyloP100

3.1

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

Sift4G

Benign

0.37

Vest4

0.70

MutPred

0.19

Gain of disorder (P = 0.1024)

MVP

0.83

MPC

0.34

ClinPred

0.91

GERP RS

3.6

Varity_R

0.82

gMVP

0.47

Mutation Taster

=18/82

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over