NM_001349253.2:c.2725G>A

Variant names:

• chr3-38894643-C-T
• rs33985936
• NM_001349253.2:c.2725G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349253.2(SCN11A):​c.2725G>A​(p.Val909Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,770 control chromosomes in the GnomAD database, including 45,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V909F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.20 (3478 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42277 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.51
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076617897).
• BP6: Variant 3-38894643-C-T is Benign according to our data. Variant chr3-38894643-C-T is described in ClinVar as [Benign]. Clinvar id is 260335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.2725G>A	p.Val909Ile	missense_variant	Exon 19 of 30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.2725G>A	p.Val909Ile	missense_variant	Exon 19 of 30	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30746 AN: 152026 Hom.: 3480 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.221 AC: 55576 AN: 251334 AF XY: 0.221

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.275

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.236 AC: 345595 AN: 1461626 Hom.: 42277 Cov.: 34 AF XY: 0.235 AC XY: 170820 AN XY: 727108

African (AFR) AF: 0.112 AC: 3759 AN: 33476

American (AMR) AF: 0.272 AC: 12158 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5561 AN: 26132

East Asian (EAS) AF: 0.102 AC: 4031 AN: 39700

South Asian (SAS) AF: 0.178 AC: 15311 AN: 86238

European-Finnish (FIN) AF: 0.240 AC: 12845 AN: 53416

Middle Eastern (MID) AF: 0.192 AC: 1107 AN: 5768

European-Non Finnish (NFE) AF: 0.249 AC: 277368 AN: 1111812

Other (OTH) AF: 0.223 AC: 13455 AN: 60378

GnomAD4 genome AF: 0.202 AC: 30753 AN: 152144 Hom.: 3478 Cov.: 32 AF XY: 0.202 AC XY: 15048 AN XY: 74372

African (AFR) AF: 0.115 AC: 4783 AN: 41534

American (AMR) AF: 0.238 AC: 3632 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 713 AN: 3472

East Asian (EAS) AF: 0.122 AC: 633 AN: 5172

South Asian (SAS) AF: 0.166 AC: 801 AN: 4824

European-Finnish (FIN) AF: 0.242 AC: 2564 AN: 10574

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 17009 AN: 67968

Other (OTH) AF: 0.200 AC: 423 AN: 2112

Alfa AF: 0.229 Hom.: 13227

Bravo AF: 0.200

TwinsUK AF: 0.248 AC: 921

ALSPAC AF: 0.241 AC: 930

ESP6500AA AF: 0.126 AC: 553

ESP6500EA AF: 0.245 AC: 2108

ExAC AF: 0.219 AC: 26589

Asia WGS AF: 0.139 AC: 483 AN: 3478

EpiCase AF: 0.250

EpiControl AF: 0.246

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27224030, 28953656) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary sensory and autonomic neuropathy type 7 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0020
DANN	Benign	0.56
DEOGEN2	Benign	0.051	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.27	T;T;T
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;N;N
PhyloP100		-3.5
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.040
MPC		0.11
ClinPred		0.011	T
GERP RS		-9.1
Varity_R		0.012
gMVP		0.076
Mutation Taster		=100/0	polymorphism (auto)

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: rs33985936; hg19: chr3-38936134; COSMIC: COSV56567571;