13-39679963-AT-ATTT

Variant names:

• chr13-39679963-A-ATT
• rs397756552
• NM_020751.3:c.624-4_624-3dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_020751.3(COG6):​c.624-4_624-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,391,998 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: COG6 NM_020751.3 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 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 9.7, offset of 0 (no position change), new splice context is: tcattaatttttttttttAGttt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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.624-4_624-3dupTT		splice_acceptor intron	N/A	NP_065802.1	Q9Y2V7-1
	COG6	NM_001145079.2		c.624-4_624-3dupTT		splice_acceptor intron	N/A	NP_001138551.1	A0A140VJG7
	COG6	NR_026745.1		n.789-4_789-3dupTT		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.624-4_624-3dupTT		splice_acceptor intron	N/A	ENSP00000397441.2	Q9Y2V7-1
	COG6	ENST00000416691.6	TSL:1	c.624-4_624-3dupTT		splice_acceptor intron	N/A	ENSP00000403733.1	Q9Y2V7-2
	COG6	ENST00000356576.8	TSL:1	n.*461-4_*461-3dupTT		splice_acceptor intron	N/A	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151476 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.000121

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

GnomAD2 exomes AF: 0.0000565 AC: 13 AN: 230006 AF XY: 0.0000640

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.0000315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.0000580

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 306 AN: 1240522 Hom.: 0 Cov.: 20 AF XY: 0.000247 AC XY: 155 AN XY: 626946

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

African (AFR) AF: 0.000531 AC: 15 AN: 28232

American (AMR) AF: 0.0000459 AC: 2 AN: 43550

Ashkenazi Jewish (ASJ) AF: 0.0000814 AC: 2 AN: 24572

East Asian (EAS) AF: 0.000159 AC: 6 AN: 37720

South Asian (SAS) AF: 0.000140 AC: 11 AN: 78346

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5170

European-Non Finnish (NFE) AF: 0.000287 AC: 263 AN: 917958

Other (OTH) AF: 0.0000952 AC: 5 AN: 52544

⚠️ 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 AF: 0.0000330 AC: 5 AN: 151476 Hom.: 0 Cov.: 21 AF XY: 0.0000270 AC XY: 2 AN XY: 73948

African (AFR) AF: 0.000121 AC: 5 AN: 41250

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10444

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67810

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 308

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.43

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397756552; hg19: chr13-40254100;