rs202084411

Positions:

• chr2-166204084-A-G
• chr2-166204084-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365536.1(SCN9A):​c.4645T>C​(p.Trp1549Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00239 in 1,612,768 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (13 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.17

Genes affected

SCN9A (HGNC:10597): (sodium voltage-gated channel alpha subunit 9) This gene encodes a voltage-gated sodium channel which plays a significant role in nociception signaling. Mutations in this gene have been associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder. [provided by RefSeq, Aug 2009]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015026212).
• BP6: Variant 2-166204084-A-G is Benign according to our data. Variant chr2-166204084-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 234412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166204084-A-G is described in Lovd as [Benign]. Variant chr2-166204084-A-G is described in Lovd as [Pathogenic]. Variant chr2-166204084-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.4645T>C	p.Trp1549Arg	missense_variant	26/27	ENST00000642356.2	NP_001352465.1
SCN1A-AS1	NR_110260.1	n.611+4266A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.4645T>C	p.Trp1549Arg	missense_variant	26/27		NM_001365536.1	ENSP00000495601	P1
SCN1A-AS1	ENST00000651574.1	n.1289+4266A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152004 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00205 AC: 509 AN: 248200 Hom.: 4 AF XY: 0.00236 AC XY: 318 AN XY: 134702

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00550

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00244 AC: 3559 AN: 1460646 Hom.: 13 Cov.: 32 AF XY: 0.00264 AC XY: 1921 AN XY: 726628

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00571

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152122 Hom.: 2 Cov.: 32 AF XY: 0.00187 AC XY: 139 AN XY: 74350

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00314

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00239 Hom.: 1

Bravo AF: 0.00162

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00334 AC: 28

ExAC AF: 0.00207 AC: 250

Asia WGS AF: 0.00173 AC: 6 AN: 3474

EpiCase AF: 0.00295

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SCN9A: PP3, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	This variant is associated with the following publications: (PMID: 29176367, 29908077, 23818614, 26680203, 23292638, 23895530, 25852444, 24828792, 26284228, 24813307, 26419464, 26236192, 25250524, 21094958, 28235406, 30212743, 31780880, 30672368, 32011655, 29991710, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 02, 2016

- -

Primary erythromelalgia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 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. -

Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SCN9A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2021

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

Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Paroxysmal extreme pain disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Uncertain	0.72	.;D;.;.;D;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.61	T;.;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.81	.;L;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;.;.;.;.;D
REVEL	Uncertain	0.63
Sift	Benign	0.92	T;.;.;.;.;T
Sift4G	Benign	0.36	T;T;.;.;.;T
Vest4		0.82
MutPred		0.65		Loss of catalytic residue at L1536 (P = 0.0064);.;Loss of catalytic residue at L1536 (P = 0.0064);.;.;.;
MVP		0.72
MPC		0.24
ClinPred		0.022	T
GERP RS		4.5
Varity_R		0.60
gMVP		0.72

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: rs202084411; hg19: chr2-167060594;