dbSNP rs78953918: SCN11A:p.Thr1410Thr (chr3-38850578-C-T) – 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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1410T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 46 hom. )

Consequence

SCN11A
NM_001349253.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

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: 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=-0.59).

BP6

Variant 3-38850578-C-T is Benign according to our data. Variant chr3-38850578-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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.

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.4230G>A	p.Thr1410Thr	synonymous	Exon 29 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.4230G>A	p.Thr1410Thr	synonymous	Exon 25 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.4230G>A	p.Thr1410Thr	synonymous	Exon 29 of 30	ENSP00000307599.3	Q9UI33-1
SCN11A	ENST00000668754.1		c.4230G>A	p.Thr1410Thr	synonymous	Exon 32 of 33	ENSP00000499569.1	Q9UI33-1
SCN11A	ENST00000456224.7	TSL:5	c.4116G>A	p.Thr1372Thr	synonymous	Exon 24 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes

AF:

0.00484

AC:

736

AN:

152038

Hom.:

Cov.:

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.:

Cov.:

AF XY:

0.00573

AC XY:

4164

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.000866

AC:

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:

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:

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

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

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.:

Cov.:

AF XY:

0.00496

AC XY:

369

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41512

American (AMR)

AF:

0.00347

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00394

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0152

AC:

161

AN:

10568

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00572

AC:

389

AN:

68018

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00630

Hom.:

Bravo

AF:

0.00371

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00486

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

7.4

(source)

DANN

Benign

0.57

PhyloP100

0.30

Mutation Taster

=100/0

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