rs112707835

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001349253.2(SCN11A):​c.1097A>G​(p.Gln366Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,613,706 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00023 ( 3 hom. )

Consequence

SCN11A
NM_001349253.2 missense

Scores

1
4
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.876

Publications

0 publications found
Variant links:
Genes affected
SCN11A (HGNC:10583): (sodium voltage-gated channel alpha subunit 11) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]
SCN11A Gene-Disease associations (from GenCC):
  • autosomal dominant hereditary sensory and autonomic neuropathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • familial episodic pain syndrome with predominantly lower limb involvement
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
  • hereditary sensory and autonomic neuropathy type 7
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
  • sodium channelopathy-related small fiber neuropathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.066485494).
BP6
Variant 3-38910070-T-C is Benign according to our data. Variant chr3-38910070-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 541590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000164 (25/152204) while in subpopulation SAS AF = 0.00145 (7/4816). AF 95% confidence interval is 0.000682. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
BS2
High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN11ANM_001349253.2 linkc.1097A>G p.Gln366Arg missense_variant Exon 12 of 30 ENST00000302328.9 NP_001336182.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN11AENST00000302328.9 linkc.1097A>G p.Gln366Arg missense_variant Exon 12 of 30 5 NM_001349253.2 ENSP00000307599.3 Q9UI33-1

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152086
Hom.:
0
Cov.:
31
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:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000255
AC:
64
AN:
250834
AF XY:
0.000325
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000203
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000234
AC:
342
AN:
1461502
Hom.:
3
Cov.:
31
AF XY:
0.000286
AC XY:
208
AN XY:
727032
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33448
American (AMR)
AF:
0.000134
AC:
6
AN:
44664
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26124
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39660
South Asian (SAS)
AF:
0.00150
AC:
129
AN:
86224
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53398
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5764
European-Non Finnish (NFE)
AF:
0.000178
AC:
198
AN:
1111844
Other (OTH)
AF:
0.0000663
AC:
4
AN:
60376
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
20
41
61
82
102
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.000164
AC:
25
AN:
152204
Hom.:
0
Cov.:
31
AF XY:
0.000148
AC XY:
11
AN XY:
74424
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41530
American (AMR)
AF:
0.00
AC:
0
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000250
AC:
17
AN:
67982
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.000169
Hom.:
0
Bravo
AF:
0.000106
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000231
AC:
28
EpiCase
AF:
0.000327
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Nov 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SCN11A: BS1 -

Feb 20, 2020
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
May 11, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Benign:1
Nov 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.84
D;.;.
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.85
D;D;D
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.066
T;T;T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
0.64
N;N;N
PhyloP100
0.88
PrimateAI
Benign
0.22
T
PROVEAN
Uncertain
-2.5
D;N;N
REVEL
Uncertain
0.30
Sift
Benign
0.17
T;T;T
Sift4G
Benign
0.096
T;T;T
Polyphen
0.0070
B;.;.
Vest4
0.29
MVP
0.87
MPC
0.16
ClinPred
0.054
T
GERP RS
-0.24
Varity_R
0.18
gMVP
0.69
Mutation Taster
=99/1
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs112707835; hg19: chr3-38951561; API