2-166198848-C-G

Variant names:

• chr2-166198848-C-G
• rs200410805
• NM_001365536.1:c.5791G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001365536.1(SCN9A):​c.5791G>C​(p.Asp1931His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1931V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.357
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010671705).
• BP6: Variant 2-166198848-C-G is Benign according to our data. Variant chr2-166198848-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 448296.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	NM_001365536.1	MANE Select	c.5791G>C	p.Asp1931His	missense	Exon 27 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.5758G>C	p.Asp1920His	missense	Exon 27 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.432-791C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.5791G>C	p.Asp1931His	missense	Exon 27 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.5791G>C	p.Asp1931His	missense	Exon 27 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.5758G>C	p.Asp1920His	missense	Exon 27 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

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

GnomAD2 exomes AF: 0.000273 AC: 68 AN: 248784 AF XY: 0.000244

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461474 Hom.: 0 Cov.: 32 AF XY: 0.000100 AC XY: 73 AN XY: 727016

African (AFR) AF: 0.00397 AC: 133 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111716

Other (OTH) AF: 0.000199 AC: 12 AN: 60368

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74424

African (AFR) AF: 0.00436 AC: 181 AN: 41528

American (AMR) AF: 0.000393 AC: 6 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.0000638 Hom.: 0

Bravo AF: 0.00135

ESP6500AA AF: 0.00389 AC: 15

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000331 AC: 40

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	not specified (2)
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.36
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.34
Sift	Benign	0.034	D
Sift4G	Uncertain	0.045	D
Vest4		0.069
MVP		0.57
MPC		0.14
ClinPred		0.021	T
GERP RS		5.2
Varity_R		0.095
gMVP		0.51
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs200410805; hg19: chr2-167055358;