chr13-45476222-A-T

Variant names:

• chr13-45476222-A-T
• rs1000819946
• NM_031431.4:c.196A>T

Variant summary

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

The NM_031431.4(COG3):​c.196A>T​(p.Ser66Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,856 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COG3 NM_031431.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69
• Publications: 0 publications found

Genes affected

COG3 (HGNC:18619): (component of oligomeric golgi complex 3) This gene encodes a component of the conserved oligomeric Golgi (COG) complex which is composed of eight different subunits and is required for normal Golgi morphology and localization. Defects in the COG complex result in multiple deficiencies in protein glycosylation. The protein encoded by this gene is involved in ER-Golgi transport.[provided by RefSeq, Jun 2011]

COG3 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation, type IIbb

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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=0.3431167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG3	NM_031431.4	c.196A>T	p.Ser66Cys	missense_variant	Exon 2 of 23	ENST00000349995.10	NP_113619.3
COG3	XM_047430702.1	c.196A>T	p.Ser66Cys	missense_variant	Exon 2 of 19		XP_047286658.1
COG3	XR_007063702.1	n.294A>T		non_coding_transcript_exon_variant	Exon 2 of 14
COG3	XR_429222.5	n.294A>T		non_coding_transcript_exon_variant	Exon 2 of 24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG3	ENST00000349995.10	c.196A>T	p.Ser66Cys	missense_variant	Exon 2 of 23	1	NM_031431.4	ENSP00000258654.8
COG3	ENST00000617493.1	c.196A>T	p.Ser66Cys	missense_variant	Exon 2 of 12	1		ENSP00000481332.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461662 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727142

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111962

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196A>T (p.S66C) alteration is located in exon 2 (coding exon 2) of the COG3 gene. This alteration results from a A to T substitution at nucleotide position 196, causing the serine (S) at amino acid position 66 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		6.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.12
Sift	Uncertain	0.027	D;.
Sift4G	Benign	0.11	T;D
Polyphen		1.0	D;D
Vest4		0.41
MutPred		0.32		Gain of catalytic residue at L67 (P = 5e-04);Gain of catalytic residue at L67 (P = 5e-04);
MVP		0.45
MPC		0.61
ClinPred		0.81	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.43
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1000819946; hg19: chr13-46050357;