rs36084747

Variant names:

• chr3-38921211-G-A
• rs36084747
• NM_001349253.2:c.757C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001349253.2(SCN11A):​c.757C>T​(p.Leu253Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0016 in 1,614,076 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: SCN11A NM_001349253.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.61
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 3-38921211-G-A is Benign according to our data. Variant chr3-38921211-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 474756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00546 (832/152330) while in subpopulation AFR AF = 0.0154 (640/41570). AF 95% confidence interval is 0.0144. There are 7 homozygotes in GnomAd4. There are 384 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 832 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.757C>T	p.Leu253Leu	synonymous	Exon 10 of 30	NP_001336182.1	Q9UI33-1
	SCN11A	NM_014139.3		c.757C>T	p.Leu253Leu	synonymous	Exon 6 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.757C>T	p.Leu253Leu	synonymous	Exon 10 of 30	ENSP00000307599.3	Q9UI33-1
	SCN11A	ENST00000668754.1		c.757C>T	p.Leu253Leu	synonymous	Exon 13 of 33	ENSP00000499569.1	Q9UI33-1
	SCN11A	ENST00000456224.7	TSL:5	c.757C>T	p.Leu253Leu	synonymous	Exon 6 of 25	ENSP00000416757.3	Q9UI33-3

Frequencies

GnomAD3 genomes AF: 0.00547 AC: 832 AN: 152212 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00210 AC: 526 AN: 250860 AF XY: 0.00165

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000971

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00120 AC: 1752 AN: 1461746 Hom.: 3 Cov.: 31 AF XY: 0.00114 AC XY: 828 AN XY: 727182

African (AFR) AF: 0.0148 AC: 495 AN: 33466

American (AMR) AF: 0.00376 AC: 168 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5762

European-Non Finnish (NFE) AF: 0.000724 AC: 805 AN: 1111914

Other (OTH) AF: 0.00252 AC: 152 AN: 60386

GnomAD4 genome AF: 0.00546 AC: 832 AN: 152330 Hom.: 7 Cov.: 32 AF XY: 0.00515 AC XY: 384 AN XY: 74504

African (AFR) AF: 0.0154 AC: 640 AN: 41570

American (AMR) AF: 0.00700 AC: 107 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00359 Hom.: 1

Bravo AF: 0.00671

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.4
DANN	Benign	0.79
PhyloP100		4.6
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs36084747; hg19: chr3-38962702;