3-38850744-C-T

Variant names:

• chr3-38850744-C-T
• rs555362768
• NM_001349253.2:c.4064G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001349253.2(SCN11A):​c.4064G>A​(p.Cys1355Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000696 in 1,581,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1355F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.96
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24968505).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

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.4064G>A	p.Cys1355Tyr	missense	Exon 29 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.4064G>A	p.Cys1355Tyr	missense	Exon 25 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.4064G>A	p.Cys1355Tyr	missense	Exon 29 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.4064G>A	p.Cys1355Tyr	missense	Exon 32 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.3950G>A	p.Cys1317Tyr	missense	Exon 24 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000700 AC: 10 AN: 1429026 Hom.: 0 Cov.: 29 AF XY: 0.00000424 AC XY: 3 AN XY: 707862

African (AFR) AF: 0.00 AC: 0 AN: 31918

American (AMR) AF: 0.00 AC: 0 AN: 37956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39118

South Asian (SAS) AF: 0.00 AC: 0 AN: 80348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5598

European-Non Finnish (NFE) AF: 0.00000911 AC: 10 AN: 1097312

Other (OTH) AF: 0.00 AC: 0 AN: 58980

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.62	N
PhyloP100		2.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.42
Sift	Benign	0.69	T
Sift4G	Benign	0.42	T
Polyphen		0.54	P
Vest4		0.33
MutPred		0.56		Gain of disorder (P = 0.1067)
MVP		0.93
MPC		0.79
ClinPred		0.80	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.65
Mutation Taster		=46/54	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: rs555362768; hg19: chr3-38892235;