13-39655735-G-C

Variant names:

• chr13-39655735-G-C
• rs1016478271
• NM_020751.3:c.9G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020751.3(COG6):​c.9G>C​(p.Glu3Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.800
• Publications: 0 publications found

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]

COG6 Gene-Disease associations (from GenCC):

• COG6-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049358606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 19	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 19		NP_001138551.1
COG6	XM_011535168.2	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 20		XP_011533470.1
COG6	NR_026745.1	n.109G>C		non_coding_transcript_exon_variant	Exon 1 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.9G>C	p.Glu3Asp	missense_variant	Exon 1 of 19	1	NM_020751.3	ENSP00000397441.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 3 of the COG6 protein (p.Glu3Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COG6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1011213). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0070	.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
PhyloP100		0.80
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.070	N;N;.
REVEL	Benign	0.029
Sift	Benign	0.86	T;T;.
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.19
MutPred		0.17		Gain of catalytic residue at E7 (P = 0.0323);Gain of catalytic residue at E7 (P = 0.0323);Gain of catalytic residue at E7 (P = 0.0323);
MVP		0.10
MPC		0.050
ClinPred		0.14	T
GERP RS		2.6
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.040
gMVP		0.12
Mutation Taster		=98/2	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: rs1016478271; hg19: chr13-40229872;