3-38846530-T-C

Variant names:

• chr3-38846530-T-C
• rs4234133
• NM_001349253.2:c.*164A>G

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.*164A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 611,804 control chromosomes in the GnomAD database, including 87,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26960 hom., cov: 33)
  • Exomes 𝑓: 0.51 (60234 hom.)
• Consequence: SCN11A NM_001349253.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 9 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 (BayesDel_noAF=-0.91).
• BP6: Variant 3-38846530-T-C is Benign according to our data. Variant chr3-38846530-T-C is described in ClinVar as [Benign]. Clinvar id is 1178114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.*164A>G		3_prime_UTR_variant	Exon 30 of 30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.*164A>G		3_prime_UTR_variant	Exon 30 of 30	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88345 AN: 151982 Hom.: 26915 Cov.: 33

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.508 AC: 233469 AN: 459704 Hom.: 60234 Cov.: 4 AF XY: 0.503 AC XY: 121777 AN XY: 241870

African (AFR) AF: 0.775 AC: 9759 AN: 12586

American (AMR) AF: 0.466 AC: 8774 AN: 18824

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 7521 AN: 13712

East Asian (EAS) AF: 0.515 AC: 16048 AN: 31188

South Asian (SAS) AF: 0.432 AC: 18831 AN: 43566

European-Finnish (FIN) AF: 0.506 AC: 17133 AN: 33832

Middle Eastern (MID) AF: 0.486 AC: 965 AN: 1986

European-Non Finnish (NFE) AF: 0.507 AC: 140829 AN: 277714

Other (OTH) AF: 0.518 AC: 13609 AN: 26296

GnomAD4 genome AF: 0.582 AC: 88448 AN: 152100 Hom.: 26960 Cov.: 33 AF XY: 0.574 AC XY: 42690 AN XY: 74324

African (AFR) AF: 0.786 AC: 32636 AN: 41522

American (AMR) AF: 0.471 AC: 7194 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1931 AN: 3472

East Asian (EAS) AF: 0.547 AC: 2828 AN: 5174

South Asian (SAS) AF: 0.421 AC: 2031 AN: 4820

European-Finnish (FIN) AF: 0.505 AC: 5318 AN: 10538

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34657 AN: 67968

Other (OTH) AF: 0.548 AC: 1158 AN: 2114

Alfa AF: 0.536 Hom.: 64488

Bravo AF: 0.594

Asia WGS AF: 0.489 AC: 1701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.77
PhyloP100		-1.1
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: rs4234133; hg19: chr3-38888021;