3-38846594-G-T

Variant names:

• chr3-38846594-G-T
• rs192005503
• NM_001349253.2:c.*100C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001349253.2(SCN11A):​c.*100C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 840,044 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (30 hom.)
• Consequence: SCN11A NM_001349253.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.124
• Publications: 1 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• hereditary sensory and autonomic neuropathy type 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.82).
• BP6: Variant 3-38846594-G-T is Benign according to our data. Variant chr3-38846594-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1201052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00592 (901/152182) while in subpopulation NFE AF = 0.00572 (389/68008). AF 95% confidence interval is 0.00525. There are 3 homozygotes in GnomAd4. There are 453 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 901 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349253.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	NM_001349253.2	MANE Select	c.*100C>A		3_prime_UTR	Exon 30 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.*100C>A		3_prime_UTR	Exon 26 of 26	NP_054858.2	Q9UI33-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN11A	ENST00000302328.9	TSL:5 MANE Select	c.*100C>A		3_prime_UTR	Exon 30 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.*100C>A		3_prime_UTR	Exon 33 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.*100C>A		downstream_gene	N/A	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 902 AN: 152064 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00493

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00623 AC: 4287 AN: 687862 Hom.: 30 Cov.: 9 AF XY: 0.00642 AC XY: 2306 AN XY: 359388

African (AFR) AF: 0.00638 AC: 109 AN: 17074

American (AMR) AF: 0.00399 AC: 112 AN: 28080

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 249 AN: 16036

East Asian (EAS) AF: 0.00 AC: 0 AN: 35704

South Asian (SAS) AF: 0.00463 AC: 254 AN: 54806

European-Finnish (FIN) AF: 0.0165 AC: 815 AN: 49452

Middle Eastern (MID) AF: 0.00977 AC: 24 AN: 2456

European-Non Finnish (NFE) AF: 0.00552 AC: 2485 AN: 450432

Other (OTH) AF: 0.00707 AC: 239 AN: 33822

GnomAD4 genome AF: 0.00592 AC: 901 AN: 152182 Hom.: 3 Cov.: 32 AF XY: 0.00609 AC XY: 453 AN XY: 74420

African (AFR) AF: 0.00491 AC: 204 AN: 41508

American (AMR) AF: 0.00412 AC: 63 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4810

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10596

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00572 AC: 389 AN: 68008

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00760 Hom.: 1

Bravo AF: 0.00499

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.74
DANN	Benign	0.42
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

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: rs192005503; hg19: chr3-38888085;