chr2-166204108-G-T

Variant summary

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

The NM_001365536.1(SCN9A):​c.4621C>A​(p.Gln1541Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -4.80

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

Genome browser will be placed here

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=0.046516).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN9ANM_001365536.1 linkc.4621C>A p.Gln1541Lys missense_variant Exon 26 of 27 ENST00000642356.2 NP_001352465.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN9AENST00000642356.2 linkc.4621C>A p.Gln1541Lys missense_variant Exon 26 of 27 NM_001365536.1 ENSP00000495601.1 Q15858-1
SCN9AENST00000303354.11 linkc.4621C>A p.Gln1541Lys missense_variant Exon 26 of 27 5 ENSP00000304748.7 Q15858-1
SCN9AENST00000409672.5 linkc.4588C>A p.Gln1530Lys missense_variant Exon 26 of 27 5 ENSP00000386306.1 Q15858-3
SCN9AENST00000645907.1 linkc.4588C>A p.Gln1530Lys missense_variant Exon 26 of 27 ENSP00000495983.1 Q15858-4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151904
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1460628
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726588
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000897
AC:
3
AN:
33448
American (AMR)
AF:
0.00
AC:
0
AN:
44632
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26098
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39592
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86210
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53316
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111252
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60320
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.350
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000658
AC:
1
AN:
151904
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74158
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41408
American (AMR)
AF:
0.00
AC:
0
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67850
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Uncertain:1
Oct 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1530 of the SCN9A protein (p.Gln1530Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN9A-related conditions. ClinVar contains an entry for this variant (Variation ID: 424146). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SCN9A protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Mar 08, 2017
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

A variant of uncertain significance has been identified in the SCN9A gene. The Q1530K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q1530K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Q1530K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Missense variants in nearby residues (M1532I and W1538R) have been reported in Human Gene Mutation Database in association with SCN9A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, this substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.086
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
0.0010
DANN
Benign
0.38
DEOGEN2
Uncertain
0.43
.;T;.;.;T;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.015
N
LIST_S2
Benign
0.12
T;.;T;T;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.047
T;T;T;T;T;T
MetaSVM
Uncertain
0.17
D
MutationAssessor
Benign
-0.47
.;N;.;.;N;N
PhyloP100
-4.8
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.070
N;.;.;.;.;N
REVEL
Uncertain
0.30
Sift
Benign
0.91
T;.;.;.;.;T
Sift4G
Benign
0.63
T;T;.;.;.;T
Vest4
0.17
MutPred
0.49
Gain of methylation at Q1530 (P = 5e-04);.;Gain of methylation at Q1530 (P = 5e-04);.;.;.;
MVP
0.45
MPC
0.15
ClinPred
0.047
T
GERP RS
-2.7
Varity_R
0.069
gMVP
0.14
Mutation Taster
=86/14
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1064796825; hg19: chr2-167060618; API