NM_002976.4:c.1685A>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002976.4(SCN7A):c.1685A>T(p.Tyr562Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,571,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y562C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SCN7A
NM_002976.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.43

Publications

7 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN7A	NM_002976.4 link	c.1685A>T	p.Tyr562Phe	missense_variant	Exon 14 of 26	ENST00000643258.1	NP_002967.2	Q01118

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN7A	ENST00000643258.1 link	c.1685A>T	p.Tyr562Phe	missense_variant	Exon 14 of 26		NM_002976.4	ENSP00000496114.1	Q01118
SCN7A	ENST00000441411.2 link	c.1685A>T	p.Tyr562Phe	missense_variant	Exon 13 of 25	1		ENSP00000403846.2	Q01118
SCN7A	ENST00000424326.5 link	n.1685A>T		non_coding_transcript_exon_variant	Exon 13 of 26	1		ENSP00000396600.1	F8WD82
SCN7A	ENST00000419992.6 link	c.1685A>T	p.Tyr562Phe	missense_variant	Exon 14 of 15	5		ENSP00000413699.2	C9JW43

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000141

AC:

AN:

1419226

Hom.:

Cov.:

AF XY:

0.00000712

AC XY:

AN XY:

701920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32634

American (AMR)

AF:

0.00

AC:

AN:

37908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

38200

South Asian (SAS)

AF:

0.00

AC:

AN:

80084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.0000184

AC:

AN:

1089446

Other (OTH)

AF:

0.00

AC:

AN:

58808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;D;D;D;D;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;.;.;.;D

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

M;M;M;M;M;.

PhyloP100

3.4

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.7

.;.;D;.;.;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.019

.;.;D;.;.;T

Sift4G

Uncertain

0.057

T;T;T;.;.;D

Polyphen

0.94

P;P;P;P;P;.

Vest4

0.45

MutPred

0.71

Loss of catalytic residue at Y562 (P = 0.2434);Loss of catalytic residue at Y562 (P = 0.2434);Loss of catalytic residue at Y562 (P = 0.2434);Loss of catalytic residue at Y562 (P = 0.2434);Loss of catalytic residue at Y562 (P = 0.2434);Loss of catalytic residue at Y562 (P = 0.2434);

MVP

0.98

MPC

0.23

ClinPred

0.98

GERP RS

4.9

Varity_R

0.40

gMVP

0.17

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over