chr2-166226650-C-T

Variant names:

• chr2-166226650-C-T
• rs149346064
• NM_001365536.1:c.4315G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365536.1(SCN9A):​c.4315G>A​(p.Val1439Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,589,422 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1439V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (12 hom.)
• Consequence: SCN9A NM_001365536.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.43
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010564268).
• BP6: Variant 2-166226650-C-T is Benign according to our data. Variant chr2-166226650-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000966 (1388/1437348) while in subpopulation MID AF = 0.0121 (69/5724). AF 95% confidence interval is 0.00977. There are 12 homozygotes in GnomAdExome4. There are 774 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,SD,AR gene

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.4315G>A	p.Val1439Ile	missense	Exon 24 of 27	NP_001352465.1	Q15858-1
	SCN9A	NM_002977.4		c.4282G>A	p.Val1428Ile	missense	Exon 24 of 27	NP_002968.2	Q15858-3
	SCN1A-AS1	NR_110260.1		n.612-21545C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN9A	ENST00000642356.2	MANE Select	c.4315G>A	p.Val1439Ile	missense	Exon 24 of 27	ENSP00000495601.1	Q15858-1
	SCN9A	ENST00000303354.11	TSL:5	c.4315G>A	p.Val1439Ile	missense	Exon 24 of 27	ENSP00000304748.7	Q15858-1
	SCN9A	ENST00000409672.5	TSL:5	c.4282G>A	p.Val1428Ile	missense	Exon 24 of 27	ENSP00000386306.1	Q15858-3

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151958 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00161 AC: 369 AN: 228762 AF XY: 0.00171

Gnomad AFR exome AF: 0.000215

Gnomad AMR exome AF: 0.000605

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000594

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.000966 AC: 1388 AN: 1437348 Hom.: 12 Cov.: 28 AF XY: 0.00109 AC XY: 774 AN XY: 712992

African (AFR) AF: 0.000122 AC: 4 AN: 32920

American (AMR) AF: 0.000590 AC: 25 AN: 42346

Ashkenazi Jewish (ASJ) AF: 0.0195 AC: 499 AN: 25638

East Asian (EAS) AF: 0.000231 AC: 9 AN: 39026

South Asian (SAS) AF: 0.00313 AC: 249 AN: 79614

European-Finnish (FIN) AF: 0.0000380 AC: 2 AN: 52656

Middle Eastern (MID) AF: 0.0121 AC: 69 AN: 5724

European-Non Finnish (NFE) AF: 0.000381 AC: 419 AN: 1099904

Other (OTH) AF: 0.00188 AC: 112 AN: 59520

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152074 Hom.: 2 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74336

African (AFR) AF: 0.000241 AC: 10 AN: 41528

American (AMR) AF: 0.000655 AC: 10 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000633 AC: 43 AN: 67932

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.000994

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000240 AC: 1

ESP6500EA AF: 0.000825 AC: 7

ExAC AF: 0.00136 AC: 164

Asia WGS AF: 0.00174 AC: 6 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	not specified (3)
-	-	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	Inborn genetic diseases (1)
-	-	1	Paroxysmal extreme pain disorder (1)
-	-	1	Primary erythromelalgia (1)
-	-	1	Small fiber neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Benign	0.60
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.88	N
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.37	N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.28
MVP		0.34
MPC		0.093
ClinPred		0.0045	T
GERP RS		4.3
Varity_R		0.058
gMVP		0.31
Mutation Taster		=95/5	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: rs149346064; hg19: chr2-167083160; COSMIC: COSV57610858;