NM_001365536.1:c.3944T>C

Variant names:

• chr2-166228953-A-G
• rs202235611
• NM_001365536.1:c.3944T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_001365536.1(SCN9A):​c.3944T>C​(p.Ile1315Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000552 in 1,613,316 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).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 5.32
• Publications: 1 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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001365536.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3111923).
• BP6: Variant 2-166228953-A-G is Benign according to our data. Variant chr2-166228953-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 331965.

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.3944T>C	p.Ile1315Thr	missense	Exon 22 of 27	NP_001352465.1
	SCN9A	NM_002977.4		c.3911T>C	p.Ile1304Thr	missense	Exon 22 of 27	NP_002968.2
	SCN1A-AS1	NR_110260.1		n.612-19242A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.3944T>C	p.Ile1315Thr	missense	Exon 22 of 27	ENSP00000495601.1
	SCN9A	ENST00000303354.11	TSL:5	c.3944T>C	p.Ile1315Thr	missense	Exon 22 of 27	ENSP00000304748.7
	SCN9A	ENST00000409672.5	TSL:5	c.3911T>C	p.Ile1304Thr	missense	Exon 22 of 27	ENSP00000386306.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000442 AC: 11 AN: 249052 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1461100 Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111374

Other (OTH) AF: 0.0000663 AC: 4 AN: 60350

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

African (AFR) AF: 0.0000482 AC: 2 AN: 41458

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000495 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1)
-	1	-	Generalized epilepsy with febrile seizures plus, type 7;C2752089:Neuropathy, hereditary sensory and autonomic, type 2A (1)
-	1	-	Inherited Erythromelalgia (1)
-	1	-	not specified (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	0.0083	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.55
Sift	Benign	0.064	T
Sift4G	Uncertain	0.0090	D
Vest4		0.30
MVP		0.86
MPC		0.15
ClinPred		0.45	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.75
Mutation Taster		=17/83	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: rs202235611; hg19: chr2-167085463;