rs883565

Variant names:

• chr3-39013826-C-T
• rs883565
• NM_001349253.2:c.-280+18554G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349253.2(SCN11A):​c.-280+18554G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,148 control chromosomes in the GnomAD database, including 6,619 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6619 hom., cov: 32)
• Consequence: SCN11A NM_001349253.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.425
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.-280+18554G>A		intron_variant	Intron 2 of 29	ENST00000302328.9	NP_001336182.1
SCN11A	NR_164473.1	n.208+18554G>A		intron_variant	Intron 2 of 2
SCN11A	XM_047447378.1	c.-19+18554G>A		intron_variant	Intron 2 of 31		XP_047303334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.-280+18554G>A		intron_variant	Intron 2 of 29	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43818 AN: 152030 Hom.: 6607 Cov.: 32

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.285

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.288 AC: 43863 AN: 152148 Hom.: 6619 Cov.: 32 AF XY: 0.285 AC XY: 21165 AN XY: 74380

African (AFR) AF: 0.361 AC: 14975 AN: 41506

American (AMR) AF: 0.250 AC: 3817 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1293 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1805 AN: 5176

South Asian (SAS) AF: 0.215 AC: 1037 AN: 4822

European-Finnish (FIN) AF: 0.249 AC: 2637 AN: 10584

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17435 AN: 67990

Other (OTH) AF: 0.289 AC: 610 AN: 2114

Alfa AF: 0.284 Hom.: 1900

Bravo AF: 0.296

Asia WGS AF: 0.303 AC: 1048 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.64
DANN	Benign	0.19
PhyloP100		-0.42

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs883565; hg19: chr3-39055317;