13-39655791-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_020751.3(COG6):c.65A>G(p.Asn22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,598,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.429

Genes affected

COG6 (HGNC:18621): (component of oligomeric golgi complex 6) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054943264).
• BP6: Variant 13-39655791-A-G is Benign according to our data. Variant chr13-39655791-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 473145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00117 (178/152306) while in subpopulation AFR AF= 0.00394 (164/41580). AF 95% confidence interval is 0.00345. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG6	NM_020751.3	c.65A>G	p.Asn22Ser	missense_variant	1/19	ENST00000455146.8
COG6	NM_001145079.2	c.65A>G	p.Asn22Ser	missense_variant	1/19
COG6	XM_011535168.2	c.65A>G	p.Asn22Ser	missense_variant	1/20
COG6	NR_026745.1	n.165A>G		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG6	ENST00000455146.8	c.65A>G	p.Asn22Ser	missense_variant	1/19	1	NM_020751.3	P1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152188 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000313 AC: 70 AN: 223308 Hom.: 0 AF XY: 0.000214 AC XY: 26 AN XY: 121460

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000506

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000154 AC: 223 AN: 1446446 Hom.: 0 Cov.: 41 AF XY: 0.000118 AC XY: 85 AN XY: 718156

Gnomad4 AFR exome AF: 0.00477

Gnomad4 AMR exome AF: 0.000254

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000308

Gnomad4 OTH exome AF: 0.000268

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152306 Hom.: 0 Cov.: 34 AF XY: 0.00110 AC XY: 82 AN XY: 74476

Gnomad4 AFR AF: 0.00394

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.00144

ESP6500AA AF: 0.00410 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000323 AC: 39

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 07, 2022

This 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). -

COG6-ongenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Uncertain	1.0
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	0.69	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.28	N;N;.
REVEL	Benign	0.025
Sift	Benign	0.50	T;T;.
Sift4G	Benign	0.81	T;T;D
Polyphen		0.0	.;B;.
Vest4		0.15
MVP		0.10
MPC		0.046
ClinPred		0.014	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.042
gMVP		0.097

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: rs149055210; hg19: chr13-40229928;