NM_006514.4:c.1668A>T

Variant names:

• chr3-38752306-T-A
• rs770276976
• NM_006514.4:c.1668A>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006514.4(SCN10A):​c.1668A>T​(p.Gln556His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,608,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q556L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SCN10A NM_006514.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.125
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13241088).
• BP6: Variant 3-38752306-T-A is Benign according to our data. Variant chr3-38752306-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 572450.
• BS2: High AC in GnomAd4 at 8 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.1668A>T	p.Gln556His	missense	Exon 12 of 28	NP_006505.4
	SCN10A	NM_001293306.2		c.1668A>T	p.Gln556His	missense	Exon 11 of 27	NP_001280235.2
	SCN10A	NM_001293307.2		c.1462-2122A>T		intron	N/A	NP_001280236.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN10A	ENST00000449082.3	TSL:1 MANE Select	c.1668A>T	p.Gln556His	missense	Exon 12 of 28	ENSP00000390600.2
	SCN10A	ENST00000643924.1		c.1668A>T	p.Gln556His	missense	Exon 11 of 27	ENSP00000495595.1
	SCN10A	ENST00000655275.1		c.1695A>T	p.Gln565His	missense	Exon 12 of 28	ENSP00000499510.1

Frequencies

GnomAD3 genomes AF: 0.0000529 AC: 8 AN: 151350 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000486 AC: 12 AN: 246998 AF XY: 0.0000674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000123 AC: 179 AN: 1457562 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 725046

African (AFR) AF: 0.0000301 AC: 1 AN: 33272

American (AMR) AF: 0.00 AC: 0 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.00 AC: 0 AN: 85510

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1109954

Other (OTH) AF: 0.0000332 AC: 2 AN: 60210

GnomAD4 genome AF: 0.0000529 AC: 8 AN: 151350 Hom.: 0 Cov.: 32 AF XY: 0.0000677 AC XY: 5 AN XY: 73828

African (AFR) AF: 0.0000243 AC: 1 AN: 41104

American (AMR) AF: 0.0000659 AC: 1 AN: 15186

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.4
DANN	Benign	0.92
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.25	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Benign	1.6	L
PhyloP100		-0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.29
Sift	Benign	0.24	T
Sift4G	Benign	0.20	T
Polyphen		0.97	D
Vest4		0.27
MutPred		0.26		Loss of glycosylation at P553 (P = 0.0103)
MVP		0.65
MPC		0.16
ClinPred		0.050	T
GERP RS		-0.30
Varity_R		0.047
gMVP		0.33
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs770276976; hg19: chr3-38793797;