3-38846594-G-T

Position:

• chr3-38846594-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 901 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN11A	NM_001349253.2	c.*100C>A		3_prime_UTR_variant	30/30	ENST00000302328.9	NP_001336182.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN11A	ENST00000302328.9	c.*100C>A		3_prime_UTR_variant	30/30	5	NM_001349253.2	ENSP00000307599	A2
SCN11A	ENST00000668754.1	c.*100C>A		3_prime_UTR_variant	33/33			ENSP00000499569	A2

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

Gnomad4 AFR exome AF: 0.00638

Gnomad4 AMR exome AF: 0.00399

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00463

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.00552

Gnomad4 OTH exome AF: 0.00707

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

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.0151

Gnomad4 NFE AF: 0.00572

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00760 Hom.: 1

Bravo AF: 0.00499

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.74
DANN	Benign	0.42

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: rs192005503; hg19: chr3-38888085;