dbSNP rs41285131: SCN11A:p.Leu1561Leu (chr3-38847387-C-G) – ACMG Classification: Benign (-21 pts)

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.4683G>C(p.Leu1561Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,116 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 7 hom., cov: 32)

Exomes 𝑓: 0.012 ( 139 hom. )

Consequence

SCN11A
NM_001349253.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0750

Publications

5 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
hereditary sensory and autonomic neuropathy type 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
sodium channelopathy-related small fiber neuropathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SCN11A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001349253.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.68).

BP6

Variant 3-38847387-C-G is Benign according to our data. Variant chr3-38847387-C-G is described in ClinVar as Benign. ClinVar VariationId is 474732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.075 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00848 (1292/152324) while in subpopulation NFE AF = 0.0145 (989/68028). AF 95% confidence interval is 0.0138. There are 7 homozygotes in GnomAd4. There are 558 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1292 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349253.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	NM_001349253.2	MANE Select	c.4683G>C	p.Leu1561Leu	synonymous	Exon 30 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.4683G>C	p.Leu1561Leu	synonymous	Exon 26 of 26	NP_054858.2	Q9UI33-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN11A	ENST00000302328.9	TSL:5 MANE Select	c.4683G>C	p.Leu1561Leu	synonymous	Exon 30 of 30	ENSP00000307599.3	Q9UI33-1
SCN11A	ENST00000668754.1		c.4683G>C	p.Leu1561Leu	synonymous	Exon 33 of 33	ENSP00000499569.1	Q9UI33-1
SCN11A	ENST00000456224.7	TSL:5	c.4569G>C	p.Leu1523Leu	synonymous	Exon 25 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes

AF:

0.00850

AC:

1293

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00713

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00842

AC:

2113

AN:

250920

AF XY:

0.00838

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00602

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00500

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0124

AC:

18171

AN:

1461792

Hom.:

139

Cov.:

AF XY:

0.0121

AC XY:

8796

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

33478

American (AMR)

AF:

0.00570

AC:

255

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00237

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00211

AC:

182

AN:

86246

European-Finnish (FIN)

AF:

0.00646

AC:

345

AN:

53398

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0150

AC:

16670

AN:

1111972

Other (OTH)

AF:

0.00984

AC:

594

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

974

1949

2923

3898

4872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.00848

AC:

1292

AN:

152324

Hom.:

Cov.:

AF XY:

0.00749

AC XY:

558

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41580

American (AMR)

AF:

0.00712

AC:

109

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0145

AC:

989

AN:

68028

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

144

215

287

359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0116

Hom.:

Bravo

AF:

0.00820

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0140

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.8

(source)

DANN

Benign

0.66

PhyloP100

-0.075

Mutation Taster

=99/1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over