NM_001349253.2:c.695C>T

Variant names:

• chr3-38925432-G-A
• rs1553641382
• NM_001349253.2:c.695C>T

Variant summary

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

The NM_001349253.2(SCN11A):​c.695C>T​(p.Ala232Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.36
• 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary sensory and autonomic neuropathy type 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	NM_001349253.2	MANE Select	c.695C>T	p.Ala232Val	missense	Exon 9 of 30	NP_001336182.1
	SCN11A	NM_014139.3		c.695C>T	p.Ala232Val	missense	Exon 5 of 26	NP_054858.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	ENST00000302328.9	TSL:5 MANE Select	c.695C>T	p.Ala232Val	missense	Exon 9 of 30	ENSP00000307599.3
	SCN11A	ENST00000668754.1		c.695C>T	p.Ala232Val	missense	Exon 12 of 33	ENSP00000499569.1
	SCN11A	ENST00000456224.7	TSL:5	c.695C>T	p.Ala232Val	missense	Exon 5 of 25	ENSP00000416757.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.66		Gain of methylation at K231 (P = 0.0455)
MVP		0.98
MPC		0.62
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.53
gMVP		0.49
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1553641382; hg19: chr3-38966923;