rs768836349

chr21-46116796-C-Tchr21-46116796-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001849.4(COL6A2):c.981C>T(p.Asn327=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,612,834 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.91

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 21-46116796-C-T is Benign according to our data. Variant chr21-46116796-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284942.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.981C>T	p.Asn327=	synonymous_variant	10/28	ENST00000300527.9
COL6A2	NM_058174.3	c.981C>T	p.Asn327=	synonymous_variant	10/28	ENST00000397763.6
COL6A2	NM_058175.3	c.981C>T	p.Asn327=	synonymous_variant	10/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.981C>T	p.Asn327=	synonymous_variant	10/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.981C>T	p.Asn327=	synonymous_variant	10/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.981C>T	p.Asn327=	synonymous_variant	9/27	5
COL6A2	ENST00000485591.1	n.637C>T		non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000340 AC: 85 AN: 250110 Hom.: 2 AF XY: 0.000228 AC XY: 31 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1460694 Hom.: 2 Cov.: 36 AF XY: 0.000138 AC XY: 100 AN XY: 726638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.000249

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	COL6A2: BP4, BP7 -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	3.4
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs768836349; hg19: chr21-47536710; COSMIC: COSV100153287; COSMIC: COSV100153287;