chr13-39724500-TTA-T

Variant names:

• chr13-39724500-TTA-T
• rs1491507046
• NM_020751.3:c.1693-7_1693-6delTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020751.3(COG6):​c.1693-7_1693-6delTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0713 in 1,227,282 control chromosomes in the GnomAD database, including 398 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 0.0030 (2 hom., cov: 0)
  • Exomes 𝑓: 0.079 (396 hom.)
• Consequence: COG6 NM_020751.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.232
• 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: 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 -16 ACMG points.

• BP6: Variant 13-39724500-TTA-T is Benign according to our data. Variant chr13-39724500-TTA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 312147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00296 (382/129218) while in subpopulation SAS AF = 0.00935 (32/3422). AF 95% confidence interval is 0.00681. There are 2 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1693-7_1693-6delTA		splice_region intron	N/A	NP_065802.1	Q9Y2V7-1
	COG6	NM_001145079.2		c.1693-7_1693-6delTA		splice_region intron	N/A	NP_001138551.1	A0A140VJG7
	COG6	NR_026745.1		n.1858-7_1858-6delTA		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG6	ENST00000455146.8	TSL:1 MANE Select	c.1693-7_1693-6delTA		splice_region intron	N/A	ENSP00000397441.2	Q9Y2V7-1
	COG6	ENST00000416691.6	TSL:1	c.1693-7_1693-6delTA		splice_region intron	N/A	ENSP00000403733.1	Q9Y2V7-2
	COG6	ENST00000356576.8	TSL:1	n.*1530-7_*1530-6delTA		splice_region intron	N/A	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 382 AN: 129132 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000955

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00658

Gnomad ASJ AF: 0.00208

Gnomad EAS AF: 0.000958

Gnomad SAS AF: 0.00935

Gnomad FIN AF: 0.00298

Gnomad MID AF: 0.0182

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.00778

GnomAD2 exomes AF: 0.0925 AC: 17430 AN: 188366 AF XY: 0.0927

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.0871

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.0484

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0841

GnomAD4 exome AF: 0.0793 AC: 87062 AN: 1098064 Hom.: 396 AF XY: 0.0813 AC XY: 44296 AN XY: 545116

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

African (AFR) AF: 0.0745 AC: 1837 AN: 24666

American (AMR) AF: 0.162 AC: 4753 AN: 29264

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2061 AN: 18214

East Asian (EAS) AF: 0.144 AC: 3847 AN: 26686

South Asian (SAS) AF: 0.134 AC: 7778 AN: 57894

European-Finnish (FIN) AF: 0.0567 AC: 2382 AN: 42020

Middle Eastern (MID) AF: 0.119 AC: 402 AN: 3372

European-Non Finnish (NFE) AF: 0.0706 AC: 60109 AN: 851804

Other (OTH) AF: 0.0882 AC: 3893 AN: 44144

⚠️ 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: 0.00296 AC: 382 AN: 129218 Hom.: 2 Cov.: 0 AF XY: 0.00307 AC XY: 192 AN XY: 62552

African (AFR) AF: 0.000953 AC: 34 AN: 35690

American (AMR) AF: 0.00666 AC: 73 AN: 10960

Ashkenazi Jewish (ASJ) AF: 0.00208 AC: 6 AN: 2882

East Asian (EAS) AF: 0.000960 AC: 4 AN: 4166

South Asian (SAS) AF: 0.00935 AC: 32 AN: 3422

European-Finnish (FIN) AF: 0.00298 AC: 27 AN: 9068

Middle Eastern (MID) AF: 0.0156 AC: 4 AN: 256

European-Non Finnish (NFE) AF: 0.00314 AC: 189 AN: 60270

Other (OTH) AF: 0.00773 AC: 13 AN: 1682

Alfa AF: 0.00166 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	COG6-congenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (1)
-	-	1	Congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1491507046; hg19: chr13-40298637; COSMIC: COSV62995331;