Genetic Variant SCN9A:p.Pro610Thr (chr2-166284599-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365536.1(SCN9A):c.1828C>A(p.Pro610Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,614,034 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. P610A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 49 hom., cov: 32)

Exomes 𝑓: 0.027 ( 625 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 2.17

Publications

34 publications found

Variant links:

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]

SCN9A links:

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

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.027049392).

BP6

Variant 2-166284599-G-T is Benign according to our data. Variant chr2-166284599-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0208 (3171/152292) while in subpopulation NFE AF = 0.0305 (2074/68024). AF 95% confidence interval is 0.0294. There are 49 homozygotes in GnomAd4. There are 1504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	NM_001365536.1	MANE Select	c.1828C>A	p.Pro610Thr	missense	Exon 12 of 27	NP_001352465.1	Q15858-1
SCN9A	NM_002977.4		c.1828C>A	p.Pro610Thr	missense	Exon 12 of 27	NP_002968.2	Q15858-3
SCN1A-AS1	NR_110260.1		n.1029+7352G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCN9A	ENST00000642356.2	MANE Select	c.1828C>A	p.Pro610Thr	missense	Exon 12 of 27	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11	TSL:5	c.1828C>A	p.Pro610Thr	missense	Exon 12 of 27	ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5	TSL:5	c.1828C>A	p.Pro610Thr	missense	Exon 12 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes

AF:

0.0209

AC:

3175

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0186

Gnomad ASJ

AF:

0.0720

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.0244

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0305

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0240

AC:

5982

AN:

249200

AF XY:

0.0251

show subpopulations

Gnomad AFR exome

AF:

0.00426

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0685

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0263

Gnomad NFE exome

AF:

0.0318

Gnomad OTH exome

AF:

0.0304

GnomAD4 exome

AF:

0.0266

AC:

38871

AN:

1461742

Hom.:

625

Cov.:

AF XY:

0.0268

AC XY:

19455

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00382

AC:

128

AN:

33480

American (AMR)

AF:

0.0138

AC:

616

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0709

AC:

1854

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0150

AC:

1290

AN:

86258

European-Finnish (FIN)

AF:

0.0263

AC:

1402

AN:

53404

Middle Eastern (MID)

AF:

0.0232

AC:

134

AN:

5768

European-Non Finnish (NFE)

AF:

0.0286

AC:

31834

AN:

1111898

Other (OTH)

AF:

0.0267

AC:

1612

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

2306

4612

6919

9225

11531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1144

2288

3432

4576

5720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0208

AC:

3171

AN:

152292

Hom.:

Cov.:

AF XY:

0.0202

AC XY:

1504

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00436

AC:

181

AN:

41558

American (AMR)

AF:

0.0186

AC:

284

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0720

AC:

250

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0155

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0244

AC:

259

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0305

AC:

2074

AN:

68024

Other (OTH)

AF:

0.0198

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

160

321

481

642

802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0270

Hom.:

242

Bravo

AF:

0.0194

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.00554

AC:

ESP6500EA

AF:

0.0294

AC:

251

ExAC

AF:

0.0239

AC:

2904

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0357

EpiControl

AF:

0.0354

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Channelopathy-associated congenital insensitivity to pain, autosomal recessive (2)

Primary erythromelalgia (3)

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

Inherited Erythromelalgia (1)

Paroxysmal extreme pain disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.34

MutationAssessor

Benign

2.0

PhyloP100

2.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.77

REVEL

Uncertain

0.33

Sift

Benign

0.076

Sift4G

Benign

0.31

Polyphen

0.0010

Vest4

0.26

MPC

0.14

ClinPred

0.0039

GERP RS

2.6

Varity_R

0.052

gMVP

0.65

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over