rs72869687

Variant names:

• chr3-38847244-G-A
• rs72869687
• NM_001349253.2:c.4826C>T

Variant summary

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

The ENST00000302328.9(SCN11A):​c.4826C>T​(p.Thr1609Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,614,022 control chromosomes in the GnomAD database, including 1,082 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. T1609A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (225 hom., cov: 32)
  • Exomes 𝑓: 0.021 (857 hom.)
• Consequence: SCN11A ENST00000302328.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.57
• Publications: 15 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=8.4528327E-4).
• BP6: Variant 3-38847244-G-A is Benign according to our data. Variant chr3-38847244-G-A is described in ClinVar as Benign. ClinVar VariationId is 474735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000302328.9. 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.4826C>T	p.Thr1609Ile	missense	Exon 30 of 30	NP_001336182.1
	SCN11A	NM_014139.3		c.4826C>T	p.Thr1609Ile	missense	Exon 26 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.4826C>T	p.Thr1609Ile	missense	Exon 30 of 30	ENSP00000307599.3
	SCN11A	ENST00000668754.1		c.4826C>T	p.Thr1609Ile	missense	Exon 33 of 33	ENSP00000499569.1
	SCN11A	ENST00000456224.7	TSL:5	c.4712C>T	p.Thr1571Ile	missense	Exon 25 of 25	ENSP00000416757.3

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5917 AN: 152196 Hom.: 227 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.00922

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0371 AC: 9321 AN: 250904 AF XY: 0.0339

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.0557

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.00782

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0205 AC: 30020 AN: 1461708 Hom.: 857 Cov.: 33 AF XY: 0.0205 AC XY: 14907 AN XY: 727148

African (AFR) AF: 0.0776 AC: 2597 AN: 33474

American (AMR) AF: 0.0510 AC: 2279 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 268 AN: 26130

East Asian (EAS) AF: 0.147 AC: 5835 AN: 39686

South Asian (SAS) AF: 0.0378 AC: 3260 AN: 86248

European-Finnish (FIN) AF: 0.00923 AC: 493 AN: 53418

Middle Eastern (MID) AF: 0.0186 AC: 107 AN: 5768

European-Non Finnish (NFE) AF: 0.0124 AC: 13738 AN: 1111890

Other (OTH) AF: 0.0239 AC: 1443 AN: 60382

GnomAD4 genome AF: 0.0389 AC: 5928 AN: 152314 Hom.: 225 Cov.: 32 AF XY: 0.0387 AC XY: 2886 AN XY: 74482

African (AFR) AF: 0.0789 AC: 3279 AN: 41560

American (AMR) AF: 0.0288 AC: 441 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.165 AC: 855 AN: 5180

South Asian (SAS) AF: 0.0419 AC: 202 AN: 4824

European-Finnish (FIN) AF: 0.00922 AC: 98 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0127 AC: 867 AN: 68030

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0239 Hom.: 391

Bravo AF: 0.0443

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.0844 AC: 372

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.0379 AC: 4602

Asia WGS AF: 0.0870 AC: 301 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	Benign	0.092
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.00085	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.15	T
Polyphen		0.0060	B
Vest4		0.019
MPC		0.15
ClinPred		0.010	T
GERP RS		-2.2
Varity_R		0.082
gMVP		0.51
Mutation Taster		=98/2	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: rs72869687; hg19: chr3-38888735; COSMIC: COSV56570947; COSMIC: COSV56570947;