2-166405578-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002976.4(SCN7A):c.*2A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,555,608 control chromosomes in the GnomAD database, including 8,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (976 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7545 hom.)
• Consequence: SCN7A NM_002976.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.97

Genes affected

SCN7A (HGNC:10594): (sodium voltage-gated channel alpha subunit 7) This gene encodes one of the many voltage-gated sodium channel proteins. For proper functioning of neurons and muscles during action potentials, voltage-gated sodium channels direct sodium ion diffusion for membrane depolarization. This sodium channel protein has some atypical characteristics; the similarity between the human and mouse proteins is lower compared to other orthologous sodium channel pairs. Also, the S4 segments, which sense voltage changes, have fewer positive charged residues that in other sodium channels; domain 4 has fewer arginine and lysine residues compared to other sodium channel proteins. Several alternatively spliced transcript variants exist, but the full-length natures of all of them remain unknown. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-166405578-T-G is Benign according to our data. Variant chr2-166405578-T-G is described in ClinVar as [Benign]. Clinvar id is 3056929.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.*2A>C		3_prime_UTR_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.*2A>C		3_prime_UTR_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.*2A>C		3_prime_UTR_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2856A>C		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16475 AN: 151932 Hom.: 977 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0588

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0858

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0972

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.103 AC: 21368 AN: 208214 Hom.: 1238 AF XY: 0.105 AC XY: 11712 AN XY: 111902

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0500

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.129

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.0904

Gnomad NFE exome AF: 0.0971

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0998 AC: 140118 AN: 1403558 Hom.: 7545 Cov.: 28 AF XY: 0.101 AC XY: 70310 AN XY: 694896

Gnomad4 AFR exome AF: 0.144

Gnomad4 AMR exome AF: 0.0544

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.131

Gnomad4 FIN exome AF: 0.0912

Gnomad4 NFE exome AF: 0.0945

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.108 AC: 16482 AN: 152050 Hom.: 976 Cov.: 32 AF XY: 0.106 AC XY: 7888 AN XY: 74346

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0587

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0858

Gnomad4 NFE AF: 0.0972

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0982 Hom.: 967

Bravo AF: 0.109

Asia WGS AF: 0.131 AC: 455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SCN7A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.5
Dann	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs16852112; hg19: chr2-167262088; COSMIC: COSV69271978;