2-166242648-A-G

Variant names:

• chr2-166242648-A-G
• rs6746030
• NM_001365536.1:c.3481T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365536.1(SCN9A):​c.3481T>C​(p.Trp1161Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,548,672 control chromosomes in the GnomAD database, including 587,761 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1161Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.88 (58696 hom., cov: 30)
  • Exomes 𝑓: 0.87 (529065 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.38

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3442258E-6).
• BP6: Variant 2-166242648-A-G is Benign according to our data. Variant chr2-166242648-A-G is described in ClinVar as [Benign]. Clinvar id is 440255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-166242648-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.3481T>C	p.Trp1161Arg	missense_variant	Exon 19 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.3481T>C	p.Trp1161Arg	missense_variant	Exon 19 of 27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.3481T>C	p.Trp1161Arg	missense_variant	Exon 19 of 27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.3448T>C	p.Trp1150Arg	missense_variant	Exon 19 of 27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.3448T>C	p.Trp1150Arg	missense_variant	Exon 19 of 27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133444 AN: 151908 Hom.: 58658 Cov.: 30

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.883

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.871

GnomAD2 exomes AF: 0.880 AC: 138994 AN: 158010 AF XY: 0.878

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 0.912

Gnomad EAS exome AF: 0.956

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.862

Gnomad OTH exome AF: 0.875

GnomAD4 exome AF: 0.870 AC: 1215240 AN: 1396646 Hom.: 529065 Cov.: 34 AF XY: 0.869 AC XY: 598906 AN XY: 688988

Gnomad4 AFR exome AF: 0.893 AC: 28155 AN: 31524

Gnomad4 AMR exome AF: 0.897 AC: 32036 AN: 35698

Gnomad4 ASJ exome AF: 0.910 AC: 22870 AN: 25126

Gnomad4 EAS exome AF: 0.950 AC: 33972 AN: 35750

Gnomad4 SAS exome AF: 0.842 AC: 66511 AN: 79000

Gnomad4 FIN exome AF: 0.894 AC: 44076 AN: 49276

Gnomad4 NFE exome AF: 0.866 AC: 931860 AN: 1076662

Gnomad4 Remaining exome AF: 0.877 AC: 50808 AN: 57924

GnomAD4 genome AF: 0.878 AC: 133538 AN: 152026 Hom.: 58696 Cov.: 30 AF XY: 0.877 AC XY: 65188 AN XY: 74304

Gnomad4 AFR AF: 0.893 AC: 0.893157 AN: 0.893157

Gnomad4 AMR AF: 0.882 AC: 0.881862 AN: 0.881862

Gnomad4 ASJ AF: 0.914 AC: 0.913545 AN: 0.913545

Gnomad4 EAS AF: 0.951 AC: 0.950813 AN: 0.950813

Gnomad4 SAS AF: 0.833 AC: 0.833333 AN: 0.833333

Gnomad4 FIN AF: 0.887 AC: 0.886862 AN: 0.886862

Gnomad4 NFE AF: 0.864 AC: 0.863551 AN: 0.863551

Gnomad4 OTH AF: 0.870 AC: 0.870388 AN: 0.870388

Alfa AF: 0.871 Hom.: 205981

Bravo AF: 0.882

TwinsUK AF: 0.873 AC: 3238

ALSPAC AF: 0.866 AC: 3338

ESP6500AA AF: 0.891 AC: 3274

ESP6500EA AF: 0.871 AC: 7029

ExAC AF: 0.852 AC: 64740

Asia WGS AF: 0.884 AC: 3076 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 89. Only high quality variants are reported. -

not provided Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary erythromelalgia Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal extreme pain disorder Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.17	.;T;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.035	T;.;T;T;T;T
MetaRNN	Benign	0.0000023	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.3	.;N;.;.;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	5.2	N;.;.;.;.;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;.;.;.;.;T
Sift4G	Benign	1.0	T;T;.;.;.;T
Vest4		0.044
MutPred		0.54		Gain of disorder (P = 0.0309);.;Gain of disorder (P = 0.0309);Gain of disorder (P = 0.0309);.;.;
MPC		0.21
ClinPred		0.0020	T
GERP RS		3.8
Varity_R		0.098
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs6746030; hg19: chr2-167099158; COSMIC: COSV57623295;