Genetic Variant SCN9A:p.Phe1452Leu (chr2-166226609-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001365536.1(SCN9A):c.4356C>A(p.Phe1452Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,433,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1452F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.87

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN9A	NM_001365536.1 link	c.4356C>A	p.Phe1452Leu	missense_variant	Exon 24 of 27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 link	c.4356C>A	p.Phe1452Leu	missense_variant	Exon 24 of 27		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 link	c.4356C>A	p.Phe1452Leu	missense_variant	Exon 24 of 27	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 link	c.4323C>A	p.Phe1441Leu	missense_variant	Exon 24 of 27	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 link	c.4323C>A	p.Phe1441Leu	missense_variant	Exon 24 of 27			ENSP00000495983.1	Q15858-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1433030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711292

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32806

American (AMR)

AF:

0.00

AC:

AN:

42846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25502

East Asian (EAS)

AF:

0.00

AC:

AN:

38974

South Asian (SAS)

AF:

0.00

AC:

AN:

79042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1096378

Other (OTH)

AF:

0.00

AC:

AN:

59256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D;.;.;D;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;.;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

.;M;.;.;M;M

PhyloP100

5.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.4

D;.;.;.;.;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.;.;.;.;D

Sift4G

Benign

0.085

T;T;.;.;.;T

Vest4

0.68

MutPred

0.78

Loss of stability (P = 0.0383);.;Loss of stability (P = 0.0383);.;.;.;

MVP

0.84

MPC

0.15

ClinPred

1.0

GERP RS

3.6

Varity_R

0.93

gMVP

0.85

Mutation Taster

=7/93

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over