rs149163316

chr16-23445077-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_153603.4(COG7):c.406G>A(p.Ala136Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000662 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A136A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: COG7 NM_153603.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 6.16

Genes affected

COG7 (HGNC:18622): (component of oligomeric golgi complex 7) The protein encoded by this gene resides in the golgi, and constitutes one of the 8 subunits of the conserved oligomeric Golgi (COG) complex, which is required for normal golgi morphology and localization. Mutations in this gene are associated with the congenital disorder of glycosylation type IIe.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03299275).
• BP6: Variant 16-23445077-C-T is Benign according to our data. Variant chr16-23445077-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 318486.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG7	NM_153603.4	c.406G>A	p.Ala136Thr	missense_variant	3/17	ENST00000307149.10
COG7	XM_017023870.2	c.211G>A	p.Ala71Thr	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG7	ENST00000307149.10	c.406G>A	p.Ala136Thr	missense_variant	3/17	1	NM_153603.4	P1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000664 AC: 167 AN: 251468 Hom.: 0 AF XY: 0.000618 AC XY: 84 AN XY: 135910

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000695

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000666 AC: 974 AN: 1461614 Hom.: 0 Cov.: 31 AF XY: 0.000637 AC XY: 463 AN XY: 727118

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000684

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000537 AC XY: 40 AN XY: 74442

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000681 Hom.: 0

Bravo AF: 0.000767

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COG7 congenital disorder of glycosylation Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jul 06, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.035	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.14	T
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.51
MPC		0.30
ClinPred		0.27	T
GERP RS		4.6
Varity_R		0.078
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

Other links and lift over

dbSNP: rs149163316; hg19: chr16-23456398;