3-38946916-CA-CAA

Position:

• chr3-38946916-CA-CAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001349253.2(SCN11A):​c.268-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,486,338 control chromosomes in the GnomAD database, including 82 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (74 hom.)
• Consequence: SCN11A NM_001349253.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.515

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 3-38946916-C-CA is Benign according to our data. Variant chr3-38946916-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 474709.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 = 0.00705 (1068/151408) while in subpopulation NFE AF= 0.0124 (843/67784). AF 95% confidence interval is 0.0117. There are 8 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1068 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.268-10dupT		intron_variant		ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.268-10dupT		intron_variant		5	NM_001349253.2	ENSP00000307599.3

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1068 AN: 151290 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00158

Gnomad AMI AF: 0.00664

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.00693

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00570

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00530

GnomAD3 exomes AF: 0.00772 AC: 1671 AN: 216350 Hom.: 8 AF XY: 0.00785 AC XY: 919 AN XY: 117124

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.00586

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00979 AC: 13070 AN: 1334930 Hom.: 74 Cov.: 20 AF XY: 0.00975 AC XY: 6518 AN XY: 668690

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00209

Gnomad4 ASJ exome AF: 0.00700

Gnomad4 EAS exome AF: 0.000283

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.00627

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00886

GnomAD4 genome AF: 0.00705 AC: 1068 AN: 151408 Hom.: 8 Cov.: 33 AF XY: 0.00673 AC XY: 498 AN XY: 73980

Gnomad4 AFR AF: 0.00157

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00693

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00570

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00524

Alfa AF: 0.0118 Hom.: 5

Bravo AF: 0.00642

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SCN11A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2023	See Variant Classification Assertion Criteria. -

SCN11A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs552650164; hg19: chr3-38988407;