2-166251875-C-T

Variant names:

• chr2-166251875-C-T
• rs74401238
• NM_001365536.1:c.3362G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.3362G>A​(p.Arg1121Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,611,986 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1121W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (51 hom., cov: 32)
  • Exomes 𝑓: 0.019 (323 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.86
• Publications: 13 publications found

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=0.002156794).
• BP6: Variant 2-166251875-C-T is Benign according to our data. Variant chr2-166251875-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0219 (3332/151996) while in subpopulation SAS AF = 0.0278 (134/4814). AF 95% confidence interval is 0.0249. There are 51 homozygotes in GnomAd4. There are 1752 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AD,SD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365536.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.3362G>A	p.Arg1121Gln	missense	Exon 18 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3329G>A	p.Arg1110Gln	missense	Exon 18 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.832C>T		non_coding_transcript_exon	Exon 7 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3362G>A	p.Arg1121Gln	missense	Exon 18 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3362G>A	p.Arg1121Gln	missense	Exon 18 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3329G>A	p.Arg1110Gln	missense	Exon 18 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3329 AN: 151878 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0419

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0204 AC: 5064 AN: 247896 AF XY: 0.0218

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00866

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.0385

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0188 AC: 27471 AN: 1459990 Hom.: 323 Cov.: 31 AF XY: 0.0193 AC XY: 13983 AN XY: 726258

African (AFR) AF: 0.0289 AC: 965 AN: 33394

American (AMR) AF: 0.00898 AC: 400 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 388 AN: 26080

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39612

South Asian (SAS) AF: 0.0283 AC: 2442 AN: 86178

European-Finnish (FIN) AF: 0.0346 AC: 1846 AN: 53336

Middle Eastern (MID) AF: 0.0344 AC: 198 AN: 5760

European-Non Finnish (NFE) AF: 0.0182 AC: 20239 AN: 1110836

Other (OTH) AF: 0.0163 AC: 984 AN: 60246

GnomAD4 genome AF: 0.0219 AC: 3332 AN: 151996 Hom.: 51 Cov.: 32 AF XY: 0.0236 AC XY: 1752 AN XY: 74278

African (AFR) AF: 0.0261 AC: 1085 AN: 41492

American (AMR) AF: 0.0106 AC: 161 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5152

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4814

European-Finnish (FIN) AF: 0.0419 AC: 444 AN: 10586

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0204 AC: 1388 AN: 67950

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0192 Hom.: 67

Bravo AF: 0.0196

TwinsUK AF: 0.0167 AC: 62

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.0326 AC: 123

ESP6500EA AF: 0.0195 AC: 160

ExAC AF: 0.0202 AC: 2441

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0188

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	1.3
DANN	Benign	0.60
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.35	N
PhyloP100		-3.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.12
Sift	Benign	0.58	T
Sift4G	Benign	0.78	T
Vest4		0.15
MPC		0.14
ClinPred		0.0019	T
GERP RS		-2.9
Varity_R		0.025
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74401238; hg19: chr2-167108385;