3-38885421-C-G

Position:

• chr3-38885421-C-G

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.2950-19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,402,202 control chromosomes in the GnomAD database, including 214,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30414 hom., cov: 31)
  • Exomes 𝑓: 0.54 (184496 hom.)
• Consequence: SCN11A NM_001349253.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.819

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 (BayesDel_noAF=-0.91).
• BP6: Variant 3-38885421-C-G is Benign according to our data. Variant chr3-38885421-C-G is described in ClinVar as [Benign]. Clinvar id is 260336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38885421-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.2950-19G>C		intron_variant		ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.2950-19G>C		intron_variant		5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93835 AN: 151938 Hom.: 30370 Cov.: 31

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.587

GnomAD3 exomes AF: 0.548 AC: 135566 AN: 247444 Hom.: 38021 AF XY: 0.541 AC XY: 72372 AN XY: 133660

Gnomad AFR exome AF: 0.841

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.555

Gnomad SAS exome AF: 0.493

Gnomad FIN exome AF: 0.558

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.543

GnomAD4 exome AF: 0.541 AC: 676275 AN: 1250144 Hom.: 184496 Cov.: 17 AF XY: 0.539 AC XY: 340679 AN XY: 632432

Gnomad4 AFR exome AF: 0.844

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.597

Gnomad4 EAS exome AF: 0.552

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.554

Gnomad4 NFE exome AF: 0.535

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.618 AC: 93935 AN: 152058 Hom.: 30414 Cov.: 31 AF XY: 0.612 AC XY: 45465 AN XY: 74332

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.605

Gnomad4 EAS AF: 0.564

Gnomad4 SAS AF: 0.486

Gnomad4 FIN AF: 0.557

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.588

Alfa AF: 0.506 Hom.: 2667

Bravo AF: 0.627

Asia WGS AF: 0.541 AC: 1881 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.47

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: rs6599266; hg19: chr3-38926912; COSMIC: COSV56572832;