rs4073113

chr3-38904069-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349253.2(SCN11A):c.1638T>C(p.Cys546=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,593,312 control chromosomes in the GnomAD database, including 343,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29075 hom., cov: 31)
  • Exomes 𝑓: 0.66 (314757 hom.)
• Consequence: SCN11A NM_001349253.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0310

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 3-38904069-A-G is Benign according to our data. Variant chr3-38904069-A-G is described in ClinVar as [Benign]. Clinvar id is 260334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38904069-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.031 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2	c.1638T>C	p.Cys546=	synonymous_variant	16/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9	c.1638T>C	p.Cys546=	synonymous_variant	16/30	5	NM_001349253.2	A2

Frequencies

GnomAD3 genomes AF: 0.614 AC: 93296 AN: 151828 Hom.: 29053 Cov.: 31

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.615

GnomAD3 exomes AF: 0.651 AC: 151841 AN: 233268 Hom.: 49610 AF XY: 0.652 AC XY: 82022 AN XY: 125738

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.626

Gnomad SAS exome AF: 0.663

Gnomad FIN exome AF: 0.676

Gnomad NFE exome AF: 0.661

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.659 AC: 950419 AN: 1441366 Hom.: 314757 Cov.: 38 AF XY: 0.659 AC XY: 471783 AN XY: 715866

Gnomad4 AFR exome AF: 0.496

Gnomad4 AMR exome AF: 0.696

Gnomad4 ASJ exome AF: 0.559

Gnomad4 EAS exome AF: 0.618

Gnomad4 SAS exome AF: 0.658

Gnomad4 FIN exome AF: 0.674

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.641

GnomAD4 genome AF: 0.614 AC: 93368 AN: 151946 Hom.: 29075 Cov.: 31 AF XY: 0.619 AC XY: 45992 AN XY: 74278

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.667

Gnomad4 FIN AF: 0.665

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.611

Alfa AF: 0.645 Hom.: 35661

Bravo AF: 0.608

Asia WGS AF: 0.606 AC: 2109 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary sensory and autonomic neuropathy type 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	3.2
Dann	Benign	0.48

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: rs4073113; hg19: chr3-38945560; COSMIC: COSV56571042;