rs148945365

Variant names:

• chr3-38867453-T-C
• rs148945365
• NM_001349253.2:c.3819A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001349253.2(SCN11A):​c.3819A>G​(p.Glu1273Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00944 in 1,591,266 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (85 hom.)
• Consequence: SCN11A NM_001349253.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -7.33
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-38867453-T-C is Benign according to our data. Variant chr3-38867453-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00714 (1087/152340) while in subpopulation NFE AF = 0.0112 (760/68030). AF 95% confidence interval is 0.0105. There are 11 homozygotes in GnomAd4. There are 496 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1087 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.3819A>G	p.Glu1273Glu	synonymous	Exon 27 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.3819A>G	p.Glu1273Glu	synonymous	Exon 23 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.3819A>G	p.Glu1273Glu	synonymous	Exon 27 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.3819A>G	p.Glu1273Glu	synonymous	Exon 30 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.3705A>G	p.Glu1235Glu	synonymous	Exon 22 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.00714 AC: 1087 AN: 152222 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00894

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00768 AC: 1763 AN: 229472 AF XY: 0.00755

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00722

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00968 AC: 13936 AN: 1438926 Hom.: 85 Cov.: 29 AF XY: 0.00945 AC XY: 6762 AN XY: 715588

African (AFR) AF: 0.00142 AC: 45 AN: 31758

American (AMR) AF: 0.00264 AC: 98 AN: 37110

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 24996

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39574

South Asian (SAS) AF: 0.00539 AC: 441 AN: 81824

European-Finnish (FIN) AF: 0.00867 AC: 461 AN: 53148

Middle Eastern (MID) AF: 0.00389 AC: 22 AN: 5656

European-Non Finnish (NFE) AF: 0.0113 AC: 12475 AN: 1105470

Other (OTH) AF: 0.00652 AC: 387 AN: 59390

GnomAD4 genome AF: 0.00714 AC: 1087 AN: 152340 Hom.: 11 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74488

African (AFR) AF: 0.00214 AC: 89 AN: 41586

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.00894 AC: 95 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0112 AC: 760 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00890 Hom.: 6

Bravo AF: 0.00639

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	SCN11A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.054
DANN	Benign	0.45
PhyloP100		-7.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs148945365; hg19: chr3-38908944;