rs151241025

Positions:

• chr2-166242623-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.3506A>C​(p.Asn1169Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,552,992 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.431

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007779449).
• BP6: Variant 2-166242623-T-G is Benign according to our data. Variant chr2-166242623-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 194947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00199 (303/152168) while in subpopulation AFR AF= 0.00701 (291/41528). AF 95% confidence interval is 0.00635. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN9A	NM_001365536.1	c.3506A>C	p.Asn1169Thr	missense_variant	19/27	ENST00000642356.2
SCN1A-AS1	NR_110260.1	n.612-5572T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN9A	ENST00000642356.2	c.3506A>C	p.Asn1169Thr	missense_variant	19/27		NM_001365536.1	P1
SCN1A-AS1	ENST00000651574.1	n.1290-5572T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 303 AN: 152050 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00703

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

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: 0.00144

GnomAD3 exomes AF: 0.000478 AC: 77 AN: 160972 Hom.: 2 AF XY: 0.000284 AC XY: 24 AN XY: 84642

Gnomad AFR exome AF: 0.00764

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000875

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000315

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000191 AC: 268 AN: 1400824 Hom.: 2 Cov.: 30 AF XY: 0.000145 AC XY: 100 AN XY: 691134

Gnomad4 AFR exome AF: 0.00665

Gnomad4 AMR exome AF: 0.000363

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.000637

GnomAD4 genome AF: 0.00199 AC: 303 AN: 152168 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74414

Gnomad4 AFR AF: 0.00701

Gnomad4 AMR AF: 0.000590

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: 0.00142

Alfa AF: 0.000311 Hom.: 1

Bravo AF: 0.00216

ESP6500AA AF: 0.00525 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000392 AC: 42

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	This variant is associated with the following publications: (PMID: 22581653) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SCN9A: BP4, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 02, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 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. -

SCN9A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.0078	T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	0.93	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.7	D;.;.;.;.;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.010	D;.;.;.;.;D
Sift4G	Uncertain	0.059	T;T;.;.;.;T
Vest4		0.29
MVP		0.62
MPC		0.17
ClinPred		0.056	T
GERP RS		2.3
Varity_R		0.27
gMVP		0.16

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: rs151241025; hg19: chr2-167099133;