rs199653503

Positions:

• chr2-166277091-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001365536.1(SCN9A):​c.2766C>T​(p.Arg922Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,968 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (3 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: SCN9A NM_001365536.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -4.40

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:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-166277091-G-A is Benign according to our data. Variant chr2-166277091-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286518.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-4.4 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN9A	NM_001365536.1	c.2766C>T	p.Arg922Arg	synonymous_variant	16/27	ENST00000642356.2	NP_001352465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN9A	ENST00000642356.2	c.2766C>T	p.Arg922Arg	synonymous_variant	16/27		NM_001365536.1	ENSP00000495601.1
SCN9A	ENST00000303354.11	c.2766C>T	p.Arg922Arg	synonymous_variant	16/27	5		ENSP00000304748.7
SCN9A	ENST00000409672.5	c.2733C>T	p.Arg911Arg	synonymous_variant	16/27	5		ENSP00000386306.1
SCN9A	ENST00000645907.1	c.2733C>T	p.Arg911Arg	synonymous_variant	16/27			ENSP00000495983.1

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152026 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251164 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135728

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48 AN XY: 727214

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000868 AC: 132 AN: 152144 Hom.: 3 Cov.: 32 AF XY: 0.000713 AC XY: 53 AN XY: 74352

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.000937

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 25, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 21, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.78
DANN	Benign	0.81

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: rs199653503; hg19: chr2-167133601; COSMIC: COSV57611280; COSMIC: COSV57611280;