3-38950315-G-C

Variant names:

• chr3-38950315-G-C
• rs201111033
• NM_001349253.2:c.48C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001349253.2(SCN11A):​c.48C>G​(p.Phe16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F16F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26910436).

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.48C>G	p.Phe16Leu	missense	Exon 5 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.48C>G	p.Phe16Leu	missense	Exon 1 of 26	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.48C>G	p.Phe16Leu	missense	Exon 5 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.48C>G	p.Phe16Leu	missense	Exon 8 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.48C>G	p.Phe16Leu	missense	Exon 1 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.012
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.43
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.35	B
Vest4		0.49
MutPred		0.55		Loss of helix (P = 0.0444)
MVP		0.95
MPC		0.67
ClinPred		0.97	D
GERP RS		4.2
PromoterAI		-0.11	Neutral
Varity_R		0.27
gMVP		0.63
Mutation Taster		=39/61	disease causing

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: rs201111033; hg19: chr3-38991806;