2-166305834-C-T

Variant names:

• chr2-166305834-C-T
• rs73969684
• NM_001365536.1:c.554G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.554G>A​(p.Arg185His) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,613,182 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 0.0054 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:13
• Conservation: PhyloP100: 6.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01727277).
• BP6: Variant 2-166305834-C-T is Benign according to our data. Variant chr2-166305834-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 157596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166305834-C-T is described in Lovd as [Benign]. Variant chr2-166305834-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00541 (821/151808) while in subpopulation AFR AF= 0.0138 (572/41408). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.554G>A	p.Arg185His	missense_variant	Exon 5 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.554G>A	p.Arg185His	missense_variant	Exon 5 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.554G>A	p.Arg185His	missense_variant	Exon 5 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.554G>A	p.Arg185His	missense_variant	Exon 5 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.554G>A	p.Arg185His	missense_variant	Exon 5 of 27			ENSP00000495983.1
SCN9A	ENST00000454569.6	c.554G>A	p.Arg185His	missense_variant	Exon 5 of 15	1		ENSP00000413212.2
SCN9A	ENST00000452182.2	c.554G>A	p.Arg185His	missense_variant	Exon 6 of 11	1		ENSP00000393141.2

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 820 AN: 151690 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.00218

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00280 AC: 698 AN: 249044 Hom.: 3 AF XY: 0.00261 AC XY: 353 AN XY: 135114

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00417

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00288

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00209 AC: 3049 AN: 1461374 Hom.: 9 Cov.: 33 AF XY: 0.00199 AC XY: 1450 AN XY: 726984

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00219

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00272

Gnomad4 NFE exome AF: 0.00185

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00541 AC: 821 AN: 151808 Hom.: 6 Cov.: 31 AF XY: 0.00520 AC XY: 386 AN XY: 74208

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.00218

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00249 Hom.: 3

Bravo AF: 0.00541

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.0135 AC: 50

ESP6500EA AF: 0.00219 AC: 18

ExAC AF: 0.00330 AC: 399

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN9A: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Mar 20, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 05, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Small fiber neuropathy Pathogenic:1 Benign:1

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Pathogenic:1 Benign:1

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Primary erythromelalgia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;.;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;D;D;D
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.8	H;H;H;.;H;H;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.8	D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D;.;.
Polyphen		1.0	.;D;.;.;D;.;.;.
Vest4		0.92
MVP		0.92
MPC		0.62
ClinPred		0.11	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.91

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: rs73969684; hg19: chr2-167162344; COSMIC: COSV57610109; COSMIC: COSV57610109;