rs143552154

chr3-38871698-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001349253.2(SCN11A):c.3506A>G(p.Asn1169Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,602,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: SCN11A NM_001349253.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.28

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16554636).
• BP6: Variant 3-38871698-T-C is Benign according to our data. Variant chr3-38871698-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 474720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN11A	NM_001349253.2	c.3506A>G	p.Asn1169Ser	missense_variant	25/30	ENST00000302328.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN11A	ENST00000302328.9	c.3506A>G	p.Asn1169Ser	missense_variant	25/30	5	NM_001349253.2	A2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000362 AC: 86 AN: 237782 Hom.: 0 AF XY: 0.000358 AC XY: 46 AN XY: 128320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000959

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000264 AC: 383 AN: 1450650 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 188 AN XY: 721324

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000273

Gnomad4 OTH exome AF: 0.000451

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74294

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000227 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000494 AC: 60

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.68
MVP		0.97
MPC		0.48
ClinPred		0.27	T
GERP RS		4.9
Varity_R		0.60
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs143552154; hg19: chr3-38913189;