13-39723394-G-C

Position:

• chr13-39723394-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_020751.3(COG6):​c.1646G>C​(p.Gly549Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,106 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. G549V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-39723394-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG6	NM_020751.3	c.1646G>C	p.Gly549Ala	missense_variant	16/19	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.1646G>C	p.Gly549Ala	missense_variant	16/19		NP_001138551.1
COG6	XM_011535168.2	c.1646G>C	p.Gly549Ala	missense_variant	16/20		XP_011533470.1
COG6	NR_026745.1	n.1811G>C		non_coding_transcript_exon_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.1646G>C	p.Gly549Ala	missense_variant	16/19	1	NM_020751.3	ENSP00000397441	P1
COG6	ENST00000416691.5	c.1646G>C	p.Gly549Ala	missense_variant	16/19	1		ENSP00000403733
COG6	ENST00000356576.8	c.*1483G>C		3_prime_UTR_variant, NMD_transcript_variant	17/20	1		ENSP00000348983

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250770 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459106 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.78	.;P
Vest4		0.70
MutPred		0.78		Gain of catalytic residue at Y552 (P = 0.0073);Gain of catalytic residue at Y552 (P = 0.0073);
MVP		0.81
MPC		0.17
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.75

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: rs387906959; hg19: chr13-40297531;