rs6599001

Variant names:

• chr3-39032660-T-C
• rs6599001
• NM_001349253.2:c.-403-157A>G

Variant summary

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

The NM_001349253.2(SCN11A):​c.-403-157A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,228 control chromosomes in the GnomAD database, including 1,761 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 0.14 (1761 hom., cov: 32)
• Consequence: SCN11A NM_001349253.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 10 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.-403-157A>G		intron_variant	Intron 1 of 29	ENST00000302328.9	NP_001336182.1
SCN11A	NR_164473.1	n.85-157A>G		intron_variant	Intron 1 of 2
SCN11A	XM_047447378.1	c.-142-157A>G		intron_variant	Intron 1 of 31		XP_047303334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.-403-157A>G		intron_variant	Intron 1 of 29	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21497 AN: 152110 Hom.: 1760 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.139

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

GnomAD4 genome AF: 0.141 AC: 21507 AN: 152228 Hom.: 1761 Cov.: 32 AF XY: 0.137 AC XY: 10191 AN XY: 74432

African (AFR) AF: 0.216 AC: 8960 AN: 41532

American (AMR) AF: 0.160 AC: 2445 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3470

East Asian (EAS) AF: 0.133 AC: 690 AN: 5190

South Asian (SAS) AF: 0.0813 AC: 392 AN: 4820

European-Finnish (FIN) AF: 0.0560 AC: 594 AN: 10598

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7532 AN: 68002

Other (OTH) AF: 0.138 AC: 291 AN: 2114

Alfa AF: 0.117 Hom.: 632

Bravo AF: 0.156

Asia WGS AF: 0.112 AC: 388 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.4
DANN	Benign	0.68
PhyloP100		0.035

Splicing

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

Other links and lift over

dbSNP: rs6599001; hg19: chr3-39074151;