chr3-38850578-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001349253.2(SCN11A):​c.4230G>A​(p.Thr1410Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,613,782 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0056 ( 46 hom. )

Consequence

SCN11A
NM_001349253.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.301

Publications

3 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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.59).
BP6
Variant 3-38850578-C-T is Benign according to our data. Variant chr3-38850578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.301 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00483 (735/152156) while in subpopulation NFE AF = 0.00572 (389/68018). AF 95% confidence interval is 0.00525. There are 2 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 735 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN11ANM_001349253.2 linkc.4230G>A p.Thr1410Thr synonymous_variant Exon 29 of 30 ENST00000302328.9 NP_001336182.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN11AENST00000302328.9 linkc.4230G>A p.Thr1410Thr synonymous_variant Exon 29 of 30 5 NM_001349253.2 ENSP00000307599.3 Q9UI33-1

Frequencies

GnomAD3 genomes
AF:
0.00484
AC:
736
AN:
152038
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00109
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00347
Gnomad ASJ
AF:
0.0164
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00394
Gnomad FIN
AF:
0.0152
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00573
Gnomad OTH
AF:
0.00335
GnomAD2 exomes
AF:
0.00613
AC:
1539
AN:
251082
AF XY:
0.00604
show subpopulations
Gnomad AFR exome
AF:
0.00117
Gnomad AMR exome
AF:
0.00309
Gnomad ASJ exome
AF:
0.0161
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.0164
Gnomad NFE exome
AF:
0.00613
Gnomad OTH exome
AF:
0.00702
GnomAD4 exome
AF:
0.00565
AC:
8252
AN:
1461626
Hom.:
46
Cov.:
31
AF XY:
0.00573
AC XY:
4164
AN XY:
727128
show subpopulations
African (AFR)
AF:
0.000866
AC:
29
AN:
33476
American (AMR)
AF:
0.00367
AC:
164
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0156
AC:
408
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.00485
AC:
418
AN:
86254
European-Finnish (FIN)
AF:
0.0164
AC:
875
AN:
53414
Middle Eastern (MID)
AF:
0.00815
AC:
47
AN:
5766
European-Non Finnish (NFE)
AF:
0.00536
AC:
5957
AN:
1111800
Other (OTH)
AF:
0.00586
AC:
354
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
408
817
1225
1634
2042
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
220
440
660
880
1100
<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:
0.00483
AC:
735
AN:
152156
Hom.:
2
Cov.:
33
AF XY:
0.00496
AC XY:
369
AN XY:
74396
show subpopulations
African (AFR)
AF:
0.00108
AC:
45
AN:
41512
American (AMR)
AF:
0.00347
AC:
53
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.0164
AC:
57
AN:
3470
East Asian (EAS)
AF:
0.000194
AC:
1
AN:
5166
South Asian (SAS)
AF:
0.00394
AC:
19
AN:
4818
European-Finnish (FIN)
AF:
0.0152
AC:
161
AN:
10568
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.00572
AC:
389
AN:
68018
Other (OTH)
AF:
0.00332
AC:
7
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
38
76
115
153
191
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00630
Hom.:
2
Bravo
AF:
0.00371
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00534
EpiControl
AF:
0.00486

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Oct 23, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

SCN11A: BP4, BP7, BS1, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:2
-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Benign:2
Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 13, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Jul 11, 2019
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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.59
CADD
Benign
7.4
DANN
Benign
0.57
PhyloP100
0.30
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs78953918; hg19: chr3-38892069; COSMIC: COSV56576672; API