rs36084747

Positions:

• chr3-38921211-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001349253.2(SCN11A):​c.757C>T​(p.Leu253=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 474756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38921211-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 832 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.757C>T	p.Leu253=	synonymous_variant	10/30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.757C>T	p.Leu253=	synonymous_variant	10/30	5	NM_001349253.2	ENSP00000307599	A2

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

GnomAD3 exomes AF: 0.00210 AC: 526 AN: 250860 Hom.: 2 AF XY: 0.00165 AC XY: 223 AN XY: 135554

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 SAS exome AF: 0.000131

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

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.00252

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

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00322 Hom.: 1

Bravo AF: 0.00671

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary sensory and autonomic neuropathy type 7;C3809899:Familial episodic pain syndrome with predominantly lower limb involvement Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.4
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs36084747; hg19: chr3-38962702;