7-107248493-G-T

Variant names:

• chr7-107248493-G-T
• rs151129529
• NM_006348.5:c.1756C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006348.5(COG5):​c.1756C>A​(p.His586Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,416,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. H586Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.81
• Publications: 0 publications found

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]

COG5 Gene-Disease associations (from GenCC):

• COG5-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39665157).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006348.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG5	NM_006348.5	MANE Select	c.1756C>A	p.His586Asn	missense	Exon 17 of 22	NP_006339.4
	COG5	NM_181733.4		c.1693C>A	p.His565Asn	missense	Exon 16 of 21	NP_859422.3	A0AAA9X096
	COG5	NM_001161520.2		c.1756C>A	p.His586Asn	missense	Exon 17 of 21	NP_001154992.2	A0AAA9X2X8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG5	ENST00000297135.9	TSL:1 MANE Select	c.1756C>A	p.His586Asn	missense	Exon 17 of 22	ENSP00000297135.4	Q9UP83-4
	COG5	ENST00000347053.8	TSL:1	c.1693C>A	p.His565Asn	missense	Exon 16 of 21	ENSP00000334703.3	A0AAA9X096
	COG5	ENST00000393603.7	TSL:1	c.1756C>A	p.His586Asn	missense	Exon 17 of 21	ENSP00000377228.3	A0AAA9X2X8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1416000 Hom.: 0 Cov.: 27 AF XY: 0.00000142 AC XY: 1 AN XY: 706422

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32208

American (AMR) AF: 0.00 AC: 0 AN: 43854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.00 AC: 0 AN: 84254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1075936

Other (OTH) AF: 0.00 AC: 0 AN: 58848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.49
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.071
Sift	Benign	0.47	T
Sift4G	Benign	0.27	T
Polyphen		0.097	B
Vest4		0.56
MutPred		0.33		Gain of MoRF binding (P = 0.0964)
MVP		0.50
MPC		0.059
ClinPred		0.30	T
GERP RS		4.0
Varity_R		0.054
gMVP		0.26
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs151129529; hg19: chr7-106888938;