rs7565062

Variant names:

• chr2-166477575-G-T
• rs7565062
• NM_002976.4:c.122C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-166477575-G-T
• chr2-166477575-G-A
• chr2-166477575-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002976.4(SCN7A):​c.122C>A​(p.Thr41Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 1,582,236 control chromosomes in the GnomAD database, including 375,869 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.70 (36788 hom., cov: 31)
  • Exomes 𝑓: 0.69 (339081 hom.)
• Consequence: SCN7A NM_002976.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.187
• Publications: 40 publications found

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]

SCN7A Gene-Disease associations (from GenCC):

• holoprosencephaly

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1589253E-6).
• BP6: Variant 2-166477575-G-T is Benign according to our data. Variant chr2-166477575-G-T is described in ClinVar as Benign. ClinVar VariationId is 3060194.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002976.4. 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
	SCN7A	NM_002976.4	MANE Select	c.122C>A	p.Thr41Asn	missense	Exon 3 of 26	NP_002967.2	Q01118
	SCN7A	NR_045628.1		n.252C>A		non_coding_transcript_exon	Exon 2 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN7A	ENST00000643258.1	MANE Select	c.122C>A	p.Thr41Asn	missense	Exon 3 of 26	ENSP00000496114.1	Q01118
	SCN7A	ENST00000441411.2	TSL:1	c.122C>A	p.Thr41Asn	missense	Exon 2 of 25	ENSP00000403846.2	Q01118
	SCN7A	ENST00000424326.5	TSL:1	n.122C>A		non_coding_transcript_exon	Exon 2 of 26	ENSP00000396600.1	F8WD82

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105360 AN: 151596 Hom.: 36751 Cov.: 31

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.706

GnomAD2 exomes AF: 0.684 AC: 139247 AN: 203490 AF XY: 0.683

Gnomad AFR exome AF: 0.741

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.678

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.678

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.688 AC: 984609 AN: 1430520 Hom.: 339081 Cov.: 43 AF XY: 0.688 AC XY: 487716 AN XY: 708490

African (AFR) AF: 0.748 AC: 24646 AN: 32948

American (AMR) AF: 0.675 AC: 26965 AN: 39940

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 17190 AN: 25524

East Asian (EAS) AF: 0.693 AC: 26941 AN: 38886

South Asian (SAS) AF: 0.710 AC: 58433 AN: 82294

European-Finnish (FIN) AF: 0.666 AC: 34487 AN: 51770

Middle Eastern (MID) AF: 0.719 AC: 4113 AN: 5718

European-Non Finnish (NFE) AF: 0.686 AC: 750554 AN: 1094272

Other (OTH) AF: 0.698 AC: 41280 AN: 59168

GnomAD4 genome AF: 0.695 AC: 105447 AN: 151716 Hom.: 36788 Cov.: 31 AF XY: 0.693 AC XY: 51392 AN XY: 74132

African (AFR) AF: 0.747 AC: 30959 AN: 41434

American (AMR) AF: 0.667 AC: 10152 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2267 AN: 3458

East Asian (EAS) AF: 0.676 AC: 3486 AN: 5160

South Asian (SAS) AF: 0.701 AC: 3376 AN: 4818

European-Finnish (FIN) AF: 0.674 AC: 7113 AN: 10548

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.674 AC: 45687 AN: 67786

Other (OTH) AF: 0.707 AC: 1484 AN: 2100

Alfa AF: 0.675 Hom.: 56508

Bravo AF: 0.699

TwinsUK AF: 0.697 AC: 2585

ALSPAC AF: 0.683 AC: 2631

ESP6500AA AF: 0.752 AC: 2755

ESP6500EA AF: 0.679 AC: 5540

ExAC AF: 0.657 AC: 78042

Asia WGS AF: 0.692 AC: 2404 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SCN7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.13
DANN	Benign	0.096
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.8	N
PhyloP100		-0.19
PrimateAI	Benign	0.24	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.021
MPC		0.037
ClinPred		0.0049	T
GERP RS		1.1
Varity_R		0.022
gMVP		0.040
Mutation Taster		=98/2	polymorphism (auto)

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: rs7565062; hg19: chr2-167334085; COSMIC: COSV69271773;