chr2-166242620-A-G

Variant names:

• chr2-166242620-A-G
• rs73019664
• NM_001365536.1:c.3509T>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.3509T>C​(p.Ile1170Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,553,390 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.682
• 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=0.008853674).
• BP6: Variant 2-166242620-A-G is Benign according to our data. Variant chr2-166242620-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130263.

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.3509T>C	p.Ile1170Thr	missense	Exon 19 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3476T>C	p.Ile1159Thr	missense	Exon 19 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.612-5575A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3509T>C	p.Ile1170Thr	missense	Exon 19 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3509T>C	p.Ile1170Thr	missense	Exon 19 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3476T>C	p.Ile1159Thr	missense	Exon 19 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152048 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000397 AC: 64 AN: 161404 AF XY: 0.000283

Gnomad AFR exome AF: 0.00386

Gnomad AMR exome AF: 0.000241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.0000314

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000151 AC: 212 AN: 1401224 Hom.: 0 Cov.: 30 AF XY: 0.000133 AC XY: 92 AN XY: 691394

African (AFR) AF: 0.00372 AC: 118 AN: 31726

American (AMR) AF: 0.000223 AC: 8 AN: 35874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 36020

South Asian (SAS) AF: 0.0000378 AC: 3 AN: 79278

European-Finnish (FIN) AF: 0.00109 AC: 54 AN: 49580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000926 AC: 10 AN: 1079746

Other (OTH) AF: 0.000310 AC: 18 AN: 58150

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152166 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74380

African (AFR) AF: 0.00380 AC: 158 AN: 41536

American (AMR) AF: 0.000262 AC: 4 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67986

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000524 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00287 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000295 AC: 32

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	-	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)
-	-	1	SCN9A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.68
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.24
Sift	Benign	0.54	T
Sift4G	Benign	0.69	T
Vest4		0.081
MVP		0.33
MPC		0.15
ClinPred		0.0054	T
GERP RS		-0.48
Varity_R		0.14
gMVP		0.20
Mutation Taster		=79/21	polymorphism

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: rs73019664; hg19: chr2-167099130;