14-39040770-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006364.4(SEC23A):​c.2104A>G​(p.Met702Val) variant causes a missense change. The variant allele was found at a frequency of 0.000471 in 1,614,212 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

SEC23A
NM_006364.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.13

Publications

19 publications found
Variant links:
Genes affected
SEC23A (HGNC:10701): (SEC23 homolog A, COPII coat complex component) The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family. It is part of a protein complex and found in the ribosome-free transitional face of the endoplasmic reticulum (ER) and associated vesicles. This protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The encoded protein is suggested to play a role in the ER-Golgi protein trafficking. [provided by RefSeq, Jul 2008]
SEC23A Gene-Disease associations (from GenCC):
  • craniolenticulosutural dysplasia
    Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18283859).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SEC23ANM_006364.4 linkc.2104A>G p.Met702Val missense_variant Exon 18 of 20 ENST00000307712.11 NP_006355.2 Q15436-1
SEC23AXM_005267262.2 linkc.2176A>G p.Met726Val missense_variant Exon 19 of 21 XP_005267319.1
SEC23AXM_011536355.4 linkc.2176A>G p.Met726Val missense_variant Exon 19 of 21 XP_011534657.1
SEC23AXM_017020928.3 linkc.2104A>G p.Met702Val missense_variant Exon 18 of 20 XP_016876417.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SEC23AENST00000307712.11 linkc.2104A>G p.Met702Val missense_variant Exon 18 of 20 1 NM_006364.4 ENSP00000306881.6 Q15436-1

Frequencies

GnomAD3 genomes
AF:
0.000328
AC:
50
AN:
152220
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000318
AC:
80
AN:
251456
AF XY:
0.000324
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000528
Gnomad OTH exome
AF:
0.000978
GnomAD4 exome
AF:
0.000486
AC:
710
AN:
1461874
Hom.:
0
Cov.:
30
AF XY:
0.000484
AC XY:
352
AN XY:
727236
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33480
American (AMR)
AF:
0.000425
AC:
19
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0000383
AC:
1
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39694
South Asian (SAS)
AF:
0.0000464
AC:
4
AN:
86256
European-Finnish (FIN)
AF:
0.000112
AC:
6
AN:
53420
Middle Eastern (MID)
AF:
0.000867
AC:
5
AN:
5768
European-Non Finnish (NFE)
AF:
0.000580
AC:
645
AN:
1112006
Other (OTH)
AF:
0.000447
AC:
27
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
41
82
124
165
206
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
24
48
72
96
120
<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:
0.000328
AC:
50
AN:
152338
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74504
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41574
American (AMR)
AF:
0.000327
AC:
5
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.0000942
AC:
1
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000603
AC:
41
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000509
Hom.:
0
Bravo
AF:
0.000400
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000280
AC:
34
EpiCase
AF:
0.000818
EpiControl
AF:
0.000948

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Craniolenticulosutural dysplasia Pathogenic:1Uncertain:1
Aug 01, 2011
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Jul 26, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SEC23A protein function. ClinVar contains an entry for this variant (Variation ID: 39521). This missense change has been observed in individual(s) with Craniolenticulosutural dysplasia (PMID: 21039434). This variant is present in population databases (rs138568622, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 702 of the SEC23A protein (p.Met702Val). Experimental studies have shown that this missense change affects SEC23A function (PMID: 22298774). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Uncertain
0.0
CADD
Benign
22
DANN
Benign
0.45
DEOGEN2
Benign
0.11
.;T;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.088
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.0098
T
MetaRNN
Benign
0.18
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.68
.;N;.
PhyloP100
6.1
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.22
Sift
Benign
1.0
T;T;T
Sift4G
Benign
1.0
T;T;T
Polyphen
0.037, 0.0020
.;B;B
Vest4
0.79
MVP
0.75
MPC
0.40
ClinPred
0.023
T
GERP RS
4.6
Varity_R
0.32
gMVP
0.52
Mutation Taster
=5/95
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs138568622; hg19: chr14-39509974; API