Genetic Variant NM_001365536.1:c.5948G>A (chr2-166198691-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001365536.1(SCN9A):c.5948G>A(p.Ser1983Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. S1983R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.222

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062453836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.5948G>A	p.Ser1983Asn	missense_variant	Exon 27 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.5948G>A	p.Ser1983Asn	missense_variant	Exon 27 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.5948G>A	p.Ser1983Asn	missense_variant	Exon 27 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.5915G>A	p.Ser1972Asn	missense_variant	Exon 27 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.5915G>A	p.Ser1972Asn	missense_variant	Exon 27 of 27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000427

AC:

AN:

234150

AF XY:

0.00000791

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:

0.00000138

AC:

AN:

1445394

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717342

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32594

American (AMR)

AF:

0.00

AC:

AN:

41726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25622

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105224

Other (OTH)

AF:

0.00

AC:

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.000153

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.21

.;T;.;.;T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.40

T;.;T;T;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.062

T;T;T;T;T;T

MetaSVM

Uncertain

-0.18

MutationAssessor

Benign

0.0

.;N;.;.;N;N

PhyloP100

-0.22

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.67

N;.;.;.;.;N

REVEL

Benign

0.25

Sift

Benign

0.066

T;.;.;.;.;T

Sift4G

Benign

0.51

T;T;.;.;.;T

Vest4

0.073

MutPred

0.19

Loss of phosphorylation at S1972 (P = 4e-04);.;Loss of phosphorylation at S1972 (P = 4e-04);.;.;.;

MVP

0.57

MPC

0.11

ClinPred

0.029

GERP RS

2.6

Varity_R

0.090

gMVP

0.10

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over