2-166406121-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002976.4(SCN7A):c.4508C>T(p.Ser1503Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000596 in 1,611,582 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (19 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.81

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 (MetaRNN=0.025952637).
• BP6: Variant 2-166406121-G-A is Benign according to our data. Variant chr2-166406121-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3055155.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000628 (916/1459700) while in subpopulation EAS AF= 0.0218 (863/39624). AF 95% confidence interval is 0.0206. There are 19 homozygotes in gnomad4_exome. There are 432 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN7A	NM_002976.4	c.4508C>T	p.Ser1503Phe	missense_variant	26/26	ENST00000643258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN7A	ENST00000643258.1	c.4508C>T	p.Ser1503Phe	missense_variant	26/26		NM_002976.4	P1
SCN7A	ENST00000441411.2	c.4508C>T	p.Ser1503Phe	missense_variant	25/25	1		P1
SCN7A	ENST00000424326.5	c.*2313C>T		3_prime_UTR_variant, NMD_transcript_variant	26/26	1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 45 AN: 151764 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00777

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000184 AC: 45 AN: 244778 Hom.: 0 AF XY: 0.000158 AC XY: 21 AN XY: 132900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00131

Gnomad EAS exome AF: 0.00164

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000628 AC: 916 AN: 1459700 Hom.: 19 Cov.: 32 AF XY: 0.000595 AC XY: 432 AN XY: 726060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151882 Hom.: 2 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74238

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00779

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SCN7A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2023

This variant is classified as likely 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;T;T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	0.52	D
PrimateAI	Benign	0.39	T
Sift4G	Pathogenic	0.0	D;D;D;.;.
Polyphen		0.028	B;B;B;B;B
Vest4		0.13
MVP		0.89
MPC		0.038
ClinPred		0.054	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.54

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: rs149649737; hg19: chr2-167262631;