rs966280936

Variant names:

• chr3-38871570-C-A
• rs966280936
• NM_001349253.2:c.3634G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38871570-C-A
• chr3-38871570-C-T

Variant summary

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

The NM_001349253.2(SCN11A):​c.3634G>T​(p.Asp1212Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.255

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=0.21581018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.3634G>T	p.Asp1212Tyr	missense_variant	Exon 25 of 30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.3634G>T	p.Asp1212Tyr	missense_variant	Exon 25 of 30	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with SCN11A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 1212 of the SCN11A protein (p.Asp1212Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.34	T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.9	L;.;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.061	T;T;D
Polyphen		0.17	B;.;.
Vest4		0.19
MutPred		0.68		Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);
MVP		0.79
MPC		0.51
ClinPred		0.71	D
GERP RS		0.86
Varity_R		0.16
gMVP		0.61

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: rs966280936; hg19: chr3-38913061; COSMIC: COSV100180821;