chr3-38846479-T-A

Variant names:

• chr3-38846479-T-A
• rs4234134
• NM_001349253.2:c.*215A>T

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.*215A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 551,160 control chromosomes in the GnomAD database, including 79,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26965 hom., cov: 33)
  • Exomes 𝑓: 0.51 (52756 hom.)
• Consequence: SCN11A NM_001349253.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.153
• Publications: 7 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=-0.9).
• BP6: Variant 3-38846479-T-A is Benign according to our data. Variant chr3-38846479-T-A is described in ClinVar as [Benign]. Clinvar id is 1273152.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.*215A>T		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.*215A>T		3_prime_UTR_variant	Exon 30 of 30	5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88361 AN: 152028 Hom.: 26920 Cov.: 33

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.546

GnomAD4 exome AF: 0.509 AC: 203216 AN: 399014 Hom.: 52756 Cov.: 3 AF XY: 0.505 AC XY: 105140 AN XY: 208274

African (AFR) AF: 0.776 AC: 9128 AN: 11764

American (AMR) AF: 0.467 AC: 8188 AN: 17540

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 6843 AN: 12488

East Asian (EAS) AF: 0.518 AC: 14961 AN: 28908

South Asian (SAS) AF: 0.429 AC: 15365 AN: 35852

European-Finnish (FIN) AF: 0.512 AC: 13052 AN: 25504

Middle Eastern (MID) AF: 0.491 AC: 891 AN: 1814

European-Non Finnish (NFE) AF: 0.507 AC: 122588 AN: 241616

Other (OTH) AF: 0.519 AC: 12200 AN: 23528

GnomAD4 genome AF: 0.581 AC: 88464 AN: 152146 Hom.: 26965 Cov.: 33 AF XY: 0.574 AC XY: 42708 AN XY: 74366

African (AFR) AF: 0.786 AC: 32644 AN: 41536

American (AMR) AF: 0.471 AC: 7202 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1929 AN: 3470

East Asian (EAS) AF: 0.547 AC: 2825 AN: 5168

South Asian (SAS) AF: 0.421 AC: 2035 AN: 4832

European-Finnish (FIN) AF: 0.504 AC: 5326 AN: 10564

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

European-Non Finnish (NFE) AF: 0.510 AC: 34656 AN: 67968

Other (OTH) AF: 0.547 AC: 1154 AN: 2110

Alfa AF: 0.446 Hom.: 1336

Bravo AF: 0.594

Asia WGS AF: 0.490 AC: 1702 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.55
PhyloP100		0.15
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: rs4234134; hg19: chr3-38887970;