13-39679963-AT-ATT

Variant names:

• chr13-39679963-A-AT
• rs397756552
• NM_020751.3:c.624-3dupT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_020751.3(COG6):​c.624-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,389,362 control chromosomes in the GnomAD database, including 35,440 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5858 hom., cov: 21)
  • Exomes 𝑓: 0.23 (29582 hom.)
• Consequence: COG6 NM_020751.3 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.428
• Publications: 2 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035967577 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.4, offset of 0 (no position change), new splice context is: atcattaattttttttttAGttt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 13-39679963-A-AT is Benign according to our data. Variant chr13-39679963-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020751.3. 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
	COG6	NM_020751.3	MANE Select	c.624-3dupT		splice_acceptor intron	N/A	NP_065802.1	Q9Y2V7-1
	COG6	NM_001145079.2		c.624-3dupT		splice_acceptor intron	N/A	NP_001138551.1	A0A140VJG7
	COG6	NR_026745.1		n.789-3dupT		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG6	ENST00000455146.8	TSL:1 MANE Select	c.624-3dupT		splice_acceptor intron	N/A	ENSP00000397441.2	Q9Y2V7-1
	COG6	ENST00000416691.6	TSL:1	c.624-3dupT		splice_acceptor intron	N/A	ENSP00000403733.1	Q9Y2V7-2
	COG6	ENST00000356576.8	TSL:1	n.*461-3dupT		splice_acceptor intron	N/A	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41422 AN: 151418 Hom.: 5851 Cov.: 21

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.240 AC: 55295 AN: 230006 AF XY: 0.242

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.190

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.231 AC: 285939 AN: 1237828 Hom.: 29582 Cov.: 20 AF XY: 0.232 AC XY: 144852 AN XY: 625694

African (AFR) AF: 0.341 AC: 9605 AN: 28162

American (AMR) AF: 0.146 AC: 6340 AN: 43486

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4570 AN: 24552

East Asian (EAS) AF: 0.287 AC: 10823 AN: 37726

South Asian (SAS) AF: 0.233 AC: 18233 AN: 78230

European-Finnish (FIN) AF: 0.271 AC: 14184 AN: 52414

Middle Eastern (MID) AF: 0.203 AC: 1048 AN: 5158

European-Non Finnish (NFE) AF: 0.228 AC: 208974 AN: 915626

Other (OTH) AF: 0.232 AC: 12162 AN: 52474

GnomAD4 genome AF: 0.274 AC: 41454 AN: 151534 Hom.: 5858 Cov.: 21 AF XY: 0.274 AC XY: 20261 AN XY: 74040

African (AFR) AF: 0.362 AC: 14979 AN: 41354

American (AMR) AF: 0.185 AC: 2820 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3466

East Asian (EAS) AF: 0.280 AC: 1444 AN: 5160

South Asian (SAS) AF: 0.263 AC: 1263 AN: 4808

European-Finnish (FIN) AF: 0.278 AC: 2900 AN: 10436

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16582 AN: 67784

Other (OTH) AF: 0.265 AC: 557 AN: 2102

Alfa AF: 0.146 Hom.: 308

Bravo AF: 0.267

Asia WGS AF: 0.278 AC: 955 AN: 3432

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	COG6-congenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (1)
-	-	1	Congenital disorder of glycosylation (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs397756552; hg19: chr13-40254100;