rs606231280

Positions:

• chr3-38909154-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5 BS2

The NM_001349253.2(SCN11A):​c.1142T>C​(p.Ile381Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I381F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP5: Variant 3-38909154-A-G is Pathogenic according to our data. Variant chr3-38909154-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157600.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr3-38909154-A-G is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2	c.1142T>C	p.Ile381Thr	missense_variant	13/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9	c.1142T>C	p.Ile381Thr	missense_variant	13/30	5	NM_001349253.2	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251210 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary sensory and autonomic neuropathy type 7 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:24776970, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, PP3_P). A missense variant is a common mechanism associated with Neuropathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2014

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2020

The p.I381T variant (also known as c.1142T>C), located in coding exon 9 of the SCN11A gene, results from a T to C substitution at nucleotide position 1142. The isoleucine at codon 381 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in two independent patients with painful peripheral neuropathy, one of whom was diagnosed with small fiber neuropathy together with large fiber dysfunction and abnormal nerve conduction studies, and the other with pure small fiber neuropathy and normal nerve conduction studies (Huang J et al. Brain, 2014 Jun;137:1627-42). Functional studies demonstrate that this alteration confers gain of function attributes on the Nav1.9 sodium channel resulting in hyperexcitability of dorsal root ganglion neurons compared to wild-type; however, pathogenic controls were not used for comparison (Huang J et al. Brain, 2014 Jun;137:1627-42). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 17, 2022

This variant is present in population databases (rs606231280, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 381 of the SCN11A protein (p.Ile381Thr). This missense change has been observed in individuals with SCN11A-related conditions (PMID: 24776970). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SCN11A function (PMID: 24776970). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 157600). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.28	B;.;.
Vest4		0.47
MutPred		0.64		Loss of stability (P = 0.0171);Loss of stability (P = 0.0171);Loss of stability (P = 0.0171);
MVP		0.93
MPC		0.28
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.54
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231280; hg19: chr3-38950645;