rs1553635601

Positions:

• chr3-38885310-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001349253.2(SCN11A):​c.3042A>T​(p.Gln1014His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.119

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18582022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2	c.3042A>T	p.Gln1014His	missense_variant	21/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9	c.3042A>T	p.Gln1014His	missense_variant	21/30	5	NM_001349253.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457788 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725608

Gnomad4 AFR exome AF: 0.00

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 29, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN11A-related disease. This sequence change replaces glutamine with histidine at codon 1014 of the SCN11A protein (p.Gln1014His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.7	L;.;L
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.027	D;D;T
Polyphen		0.60	P;.;.
Vest4		0.073
MutPred		0.48		Loss of ubiquitination at K1013 (P = 0.1016);.;Loss of ubiquitination at K1013 (P = 0.1016);
MVP		0.79
MPC		0.40
ClinPred		0.89	D
GERP RS		-3.3
Varity_R		0.19
gMVP		0.34

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: rs1553635601; hg19: chr3-38926801;