rs144270136

Variant names:

• chr3-38793743-G-A
• rs144270136
• NM_006514.4:c.268C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38793743-G-A
• chr3-38793743-G-T

Variant summary

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

The NM_006514.4(SCN10A):​c.268C>T​(p.Arg90Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,612,760 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (23 hom.)
• Consequence: SCN10A NM_006514.4 missense, splice_region
• Scores: Splicing: ADA: 0.1464
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.36
• Publications: 7 publications found

Genes affected

SCN10A (HGNC:10582): (sodium voltage-gated channel alpha subunit 10) The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

SCN10A Gene-Disease associations (from GenCC):

• sodium channelopathy-related small fiber neuropathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• episodic pain syndrome, familial, 2

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• Brugada syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Genomics England PanelApp
• Brugada syndrome 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0093019605).
• BP6: Variant 3-38793743-G-A is Benign according to our data. Variant chr3-38793743-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000796 (121/152072) while in subpopulation EAS AF = 0.0201 (104/5166). AF 95% confidence interval is 0.017. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 121 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006514.4. 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
	SCN10A	NM_006514.4	MANE Select	c.268C>T	p.Arg90Trp	missense splice_region	Exon 2 of 28	NP_006505.4
	SCN10A	NM_001293306.2		c.268C>T	p.Arg90Trp	missense splice_region	Exon 1 of 27	NP_001280235.2
	SCN10A	NM_001293307.2		c.268C>T	p.Arg90Trp	missense splice_region	Exon 1 of 26	NP_001280236.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.268C>T	p.Arg90Trp	missense splice_region	Exon 2 of 28	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.268C>T	p.Arg90Trp	missense splice_region	Exon 1 of 27	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.268C>T	p.Arg90Trp	missense splice_region	Exon 2 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.000783 AC: 119 AN: 151954 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00148 AC: 371 AN: 250390 AF XY: 0.00143

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0177

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000753 AC: 1100 AN: 1460688 Hom.: 23 Cov.: 31 AF XY: 0.000767 AC XY: 557 AN XY: 726454

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0234 AC: 930 AN: 39672

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86200

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53408

Middle Eastern (MID) AF: 0.000707 AC: 4 AN: 5658

European-Non Finnish (NFE) AF: 0.0000648 AC: 72 AN: 1111196

Other (OTH) AF: 0.000414 AC: 25 AN: 60334

GnomAD4 genome AF: 0.000796 AC: 121 AN: 152072 Hom.: 1 Cov.: 32 AF XY: 0.000996 AC XY: 74 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0201 AC: 104 AN: 5166

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4798

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000630 Hom.: 2

Bravo AF: 0.000831

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Brugada syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.92
MPC		0.28
ClinPred		0.14	T
GERP RS		1.9
PromoterAI		-0.029	Neutral
Varity_R		0.36
gMVP		0.58
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.15
dbscSNV1_RF	Benign	0.37
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: rs144270136; hg19: chr3-38835234; COSMIC: COSV107530170;