rs13059805

Positions:

• chr3-38907980-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349253.2(SCN11A):​c.1442G>A​(p.Gly481Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,608,770 control chromosomes in the GnomAD database, including 793 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 32)
  • Exomes 𝑓: 0.028 (721 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.325

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023756325).
• BP6: Variant 3-38907980-C-T is Benign according to our data. Variant chr3-38907980-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 474687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38907980-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.1442G>A	p.Gly481Glu	missense_variant	14/30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.1442G>A	p.Gly481Glu	missense_variant	14/30	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3808 AN: 152062 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0318 AC: 7812 AN: 245726 Hom.: 208 AF XY: 0.0300 AC XY: 3980 AN XY: 132574

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0722

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.00116

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.0639

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0278 AC: 40462 AN: 1456590 Hom.: 721 Cov.: 32 AF XY: 0.0272 AC XY: 19711 AN XY: 724264

Gnomad4 AFR exome AF: 0.00436

Gnomad4 AMR exome AF: 0.0672

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.0130

Gnomad4 FIN exome AF: 0.0630

Gnomad4 NFE exome AF: 0.0280

Gnomad4 OTH exome AF: 0.0232

GnomAD4 genome AF: 0.0250 AC: 3809 AN: 152180 Hom.: 72 Cov.: 32 AF XY: 0.0268 AC XY: 1997 AN XY: 74382

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.0487

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0644

Gnomad4 NFE AF: 0.0293

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0254 Hom.: 128

Bravo AF: 0.0226

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.0250 AC: 215

ExAC AF: 0.0306 AC: 3709

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0251

EpiControl AF: 0.0231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 27, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T;.;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.96	D;.;.
Vest4		0.043
MPC		0.19
ClinPred		0.011	T
GERP RS		0.62
Varity_R		0.054
gMVP		0.25

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: rs13059805; hg19: chr3-38949471; COSMIC: COSV99043384;