rs4073113

Variant names:

• chr3-38904069-A-G
• rs4073113
• NM_001349253.2:c.1638T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349253.2(SCN11A):​c.1638T>C​(p.Cys546Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,593,312 control chromosomes in the GnomAD database, including 343,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29075 hom., cov: 31)
  • Exomes 𝑓: 0.66 (314757 hom.)
• Consequence: SCN11A NM_001349253.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0310
• Publications: 31 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-38904069-A-G is Benign according to our data. Variant chr3-38904069-A-G is described in ClinVar as Benign. ClinVar VariationId is 260334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.031 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.1638T>C	p.Cys546Cys	synonymous_variant	Exon 16 of 30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.1638T>C	p.Cys546Cys	synonymous_variant	Exon 16 of 30	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93296 AN: 151828 Hom.: 29053 Cov.: 31

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.615

GnomAD2 exomes AF: 0.651 AC: 151841 AN: 233268 AF XY: 0.652

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.626

Gnomad FIN exome AF: 0.676

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.659 AC: 950419 AN: 1441366 Hom.: 314757 Cov.: 38 AF XY: 0.659 AC XY: 471783 AN XY: 715866

African (AFR) AF: 0.496 AC: 16101 AN: 32472

American (AMR) AF: 0.696 AC: 28467 AN: 40916

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 13928 AN: 24900

East Asian (EAS) AF: 0.618 AC: 24254 AN: 39230

South Asian (SAS) AF: 0.658 AC: 53970 AN: 81988

European-Finnish (FIN) AF: 0.674 AC: 35725 AN: 53012

Middle Eastern (MID) AF: 0.600 AC: 3406 AN: 5674

European-Non Finnish (NFE) AF: 0.667 AC: 736386 AN: 1103636

Other (OTH) AF: 0.641 AC: 38182 AN: 59538

GnomAD4 genome AF: 0.614 AC: 93368 AN: 151946 Hom.: 29075 Cov.: 31 AF XY: 0.619 AC XY: 45992 AN XY: 74278

African (AFR) AF: 0.506 AC: 20972 AN: 41406

American (AMR) AF: 0.669 AC: 10222 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1916 AN: 3470

East Asian (EAS) AF: 0.624 AC: 3215 AN: 5152

South Asian (SAS) AF: 0.667 AC: 3210 AN: 4812

European-Finnish (FIN) AF: 0.665 AC: 7028 AN: 10566

Middle Eastern (MID) AF: 0.534 AC: 156 AN: 292

European-Non Finnish (NFE) AF: 0.659 AC: 44767 AN: 67956

Other (OTH) AF: 0.611 AC: 1287 AN: 2106

Alfa AF: 0.641 Hom.: 44868

Bravo AF: 0.608

Asia WGS AF: 0.606 AC: 2109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial episodic pain syndrome with predominantly lower limb involvement Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary sensory and autonomic neuropathy type 7 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.2
DANN	Benign	0.48
PhyloP100		-0.031
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4073113; hg19: chr3-38945560; COSMIC: COSV56571042;