2-166306951-G-A

Position:

chr2-166306951-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001365536.1(SCN9A):c.377+5C>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000339 in 1,476,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

SCN9A
NM_001365536.1 splice_region, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 10.0

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:):

SCN1A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-166306951-G-A is Pathogenic according to our data. Variant chr2-166306951-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374103.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1 linkuse as main transcript	c.377+5C>T		splice_region_variant, intron_variant		ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
SCN9A	ENST00000642356.2 linkuse as main transcript	c.377+5C>T	splice_region_variant, intron_variant		NM_001365536.1	ENSP00000495601.1	Q15858-1
SCN9A	ENST00000303354.11 linkuse as main transcript	c.377+5C>T	splice_region_variant, intron_variant	5		ENSP00000304748.7	Q15858-1
SCN9A	ENST00000409672.5 linkuse as main transcript	c.377+5C>T	splice_region_variant, intron_variant	5		ENSP00000386306.1	Q15858-3
SCN9A	ENST00000645907.1 linkuse as main transcript	c.377+5C>T	splice_region_variant, intron_variant			ENSP00000495983.1	Q15858-4
SCN9A	ENST00000454569.6 linkuse as main transcript	c.377+5C>T	splice_region_variant, intron_variant	1		ENSP00000413212.2	A0A0C4DG82
SCN9A	ENST00000452182.2 linkuse as main transcript	c.377+5C>T	splice_region_variant, intron_variant	1		ENSP00000393141.2	H7C064

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000827

AC:

AN:

241898

Hom.:

AF XY:

0.00000764

AC XY:

AN XY:

130916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000302

AC:

AN:

1324678

Hom.:

Cov.:

AF XY:

0.00000450

AC XY:

AN XY:

666200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000303

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pain insensitivity

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 21, 2015

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2020

This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with insensitivity to pain (PMID: 28914264, 30795902). ClinVar contains an entry for this variant (Variation ID: 374103). This sequence change falls in intron 3 of the SCN9A gene. It does not directly change the encoded amino acid sequence of the SCN9A protein, but it affects a nucleotide within the consensus splice site of the intron. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.55

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.55

Position offset: 5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over