rs398122821

chr21-46125500-TTCGTCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_001849.4(COL6A2):c.1856_1861del(p.Val619_Ile620del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F618F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.72

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001849.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 21-46125500-TTCGTCA-T is Pathogenic according to our data. Variant chr21-46125500-TTCGTCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 36916.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-46125500-TTCGTCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1856_1861del	p.Val619_Ile620del	inframe_deletion	25/28	ENST00000300527.9
COL6A2	NM_058174.3	c.1856_1861del	p.Val619_Ile620del	inframe_deletion	25/28	ENST00000397763.6
COL6A2	NM_058175.3	c.1856_1861del	p.Val619_Ile620del	inframe_deletion	25/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1856_1861del	p.Val619_Ile620del	inframe_deletion	25/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1856_1861del	p.Val619_Ile620del	inframe_deletion	25/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.1856_1861del	p.Val619_Ile620del	inframe_deletion	24/27	5
COL6A2	ENST00000413758.1	c.527_532del	p.Val176_Ile177del	inframe_deletion	10/11	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460680 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ullrich congenital muscular dystrophy 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 22, 2010

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122821; hg19: chr21-47545414;