rs373324936

Variant names:

• chr3-38919930-C-G
• rs373324936
• NM_001349253.2:c.959+5G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-38919930-C-G
• chr3-38919930-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001349253.2(SCN11A):​c.959+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,457,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN11A NM_001349253.2 splice_region, intron
• Scores: Splicing: ADA: 0.5864
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• Publications: 0 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).

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.959+5G>C		splice_region intron	N/A	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.959+5G>C		splice_region intron	N/A	NP_054858.2	Q9UI33-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	ENST00000302328.9	TSL:5 MANE Select	c.959+5G>C		splice_region intron	N/A	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.959+5G>C		splice_region intron	N/A	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.959+5G>C		splice_region intron	N/A	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1457066 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725218

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107814

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: 5

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

Other links and lift over

dbSNP: rs373324936; hg19: chr3-38961421;