chr2-166281804-G-A

Variant names:

• chr2-166281804-G-A
• rs200965749
• NM_001365536.1:c.1979C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_001365536.1(SCN9A):​c.1979C>T​(p.Thr660Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000637 in 1,600,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T660T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 3.82
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75
• BP6: Variant 2-166281804-G-A is Benign according to our data. Variant chr2-166281804-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433098.

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.1979C>T	p.Thr660Met	missense	Exon 13 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.1946C>T	p.Thr649Met	missense	Exon 13 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.1029+4557G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.1979C>T	p.Thr660Met	missense	Exon 13 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.1979C>T	p.Thr660Met	missense	Exon 13 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.1946C>T	p.Thr649Met	missense	Exon 13 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.0000398 AC: 6 AN: 150628 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000560 AC: 13 AN: 232288 AF XY: 0.0000317

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.0000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000589

Gnomad FIN exome AF: 0.0000963

Gnomad NFE exome AF: 0.0000465

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000662 AC: 96 AN: 1449838 Hom.: 0 Cov.: 30 AF XY: 0.0000763 AC XY: 55 AN XY: 720986

African (AFR) AF: 0.000153 AC: 5 AN: 32612

American (AMR) AF: 0.0000238 AC: 1 AN: 42054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 83588

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000776 AC: 86 AN: 1108070

Other (OTH) AF: 0.0000334 AC: 2 AN: 59854

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150628 Hom.: 0 Cov.: 32 AF XY: 0.0000408 AC XY: 3 AN XY: 73544

African (AFR) AF: 0.000122 AC: 5 AN: 41044

American (AMR) AF: 0.00 AC: 0 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67486

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000580 AC: 7

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Inborn genetic diseases (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.55	P
Vest4		0.55
MVP		0.81
MPC		0.17
ClinPred		0.65	D
GERP RS		3.8
Varity_R		0.18
gMVP		0.63
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200965749; hg19: chr2-167138314; COSMIC: COSV57620767; COSMIC: COSV57620767;