rs35393416

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006348.5(COG5):ā€‹c.1262A>Gā€‹(p.His421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,208 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0028 ( 0 hom., cov: 32)
Exomes š‘“: 0.0039 ( 21 hom. )

Consequence

COG5
NM_006348.5 missense

Scores

18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.86
Variant links:
Genes affected
COG5 (HGNC:14857): (component of oligomeric golgi complex 5) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. The encoded protein is organized with conserved oligomeric Golgi complex components 6, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants. Mutations in this gene result in congenital disorder of glycosylation type 2I.[provided by RefSeq, Jan 2011]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0037671328).
BP6
Variant 7-107298193-T-C is Benign according to our data. Variant chr7-107298193-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 358461.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr7-107298193-T-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00281 (428/152302) while in subpopulation NFE AF= 0.00463 (315/68006). AF 95% confidence interval is 0.00421. There are 0 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COG5NM_006348.5 linkuse as main transcriptc.1262A>G p.His421Arg missense_variant 12/22 ENST00000297135.9 NP_006339.4 Q9UP83

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COG5ENST00000297135.9 linkuse as main transcriptc.1262A>G p.His421Arg missense_variant 12/221 NM_006348.5 ENSP00000297135.4 Q9UP83
COG5ENST00000347053.8 linkuse as main transcriptc.1262A>G p.His421Arg missense_variant 12/211 ENSP00000334703.3 Q9UP83
COG5ENST00000393603.7 linkuse as main transcriptc.1262A>G p.His421Arg missense_variant 12/211 ENSP00000377228.3 Q9UP83

Frequencies

GnomAD3 genomes
AF:
0.00281
AC:
427
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00268
Gnomad ASJ
AF:
0.00374
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00414
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00462
Gnomad OTH
AF:
0.00383
GnomAD3 exomes
AF:
0.00347
AC:
873
AN:
251248
Hom.:
7
AF XY:
0.00389
AC XY:
528
AN XY:
135806
show subpopulations
Gnomad AFR exome
AF:
0.000677
Gnomad AMR exome
AF:
0.00243
Gnomad ASJ exome
AF:
0.00298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00448
Gnomad FIN exome
AF:
0.000832
Gnomad NFE exome
AF:
0.00492
Gnomad OTH exome
AF:
0.00555
GnomAD4 exome
AF:
0.00394
AC:
5758
AN:
1460906
Hom.:
21
Cov.:
30
AF XY:
0.00410
AC XY:
2978
AN XY:
726736
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.00244
Gnomad4 ASJ exome
AF:
0.00310
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00488
Gnomad4 FIN exome
AF:
0.00137
Gnomad4 NFE exome
AF:
0.00419
Gnomad4 OTH exome
AF:
0.00484
GnomAD4 genome
AF:
0.00281
AC:
428
AN:
152302
Hom.:
0
Cov.:
32
AF XY:
0.00263
AC XY:
196
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000577
Gnomad4 AMR
AF:
0.00268
Gnomad4 ASJ
AF:
0.00374
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00415
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.00463
Gnomad4 OTH
AF:
0.00379
Alfa
AF:
0.00423
Hom.:
7
Bravo
AF:
0.00296
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00467
AC:
18
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00430
AC:
37
ExAC
AF:
0.00344
AC:
417
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingGeneDxJul 06, 2018- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 06, 2017- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2024COG5: BP4, BS2 -
COG5-congenital disorder of glycosylation Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
COG5-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 20, 2022This 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
0.073
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
13
DANN
Benign
0.66
DEOGEN2
Benign
0.0043
T;.;.
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.63
T;T;T
MetaRNN
Benign
0.0038
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.90
L;L;L
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.68
N;N;N
REVEL
Benign
0.043
Sift
Benign
0.34
T;T;T
Sift4G
Benign
0.37
T;T;T
Polyphen
0.0060
B;B;.
Vest4
0.31
MVP
0.53
MPC
0.064
ClinPred
0.0048
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.043
gMVP
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35393416; hg19: chr7-106938638; COSMIC: COSV99773705; API