rs34495634

Variant names:

• chr21-45989666-C-A
• rs34495634
• NM_001848.3:c.903+14C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45989666-C-A
• chr21-45989666-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.903+14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,612,936 control chromosomes in the GnomAD database, including 42,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2888 hom., cov: 33)
  • Exomes 𝑓: 0.22 (39908 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.54
• Publications: 9 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

  Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-45989666-C-A is Benign according to our data. Variant chr21-45989666-C-A is described in ClinVar as Benign. ClinVar VariationId is 93897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. 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
	COL6A1	NM_001848.3	MANE Select	c.903+14C>A		intron	N/A	NP_001839.2	P12109

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.903+14C>A		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.564+3005C>A		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26086 AN: 152060 Hom.: 2887 Cov.: 33

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.00560

Gnomad SAS AF: 0.0963

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.183 AC: 45815 AN: 250684 AF XY: 0.185

Gnomad AFR exome AF: 0.0526

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.00375

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.225 AC: 328132 AN: 1460758 Hom.: 39908 Cov.: 49 AF XY: 0.221 AC XY: 160715 AN XY: 726692

African (AFR) AF: 0.0505 AC: 1691 AN: 33480

American (AMR) AF: 0.153 AC: 6855 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4104 AN: 26136

East Asian (EAS) AF: 0.00496 AC: 197 AN: 39700

South Asian (SAS) AF: 0.109 AC: 9440 AN: 86258

European-Finnish (FIN) AF: 0.268 AC: 14035 AN: 52424

Middle Eastern (MID) AF: 0.130 AC: 750 AN: 5764

European-Non Finnish (NFE) AF: 0.251 AC: 278848 AN: 1111888

Other (OTH) AF: 0.202 AC: 12212 AN: 60384

GnomAD4 genome AF: 0.171 AC: 26094 AN: 152178 Hom.: 2888 Cov.: 33 AF XY: 0.172 AC XY: 12786 AN XY: 74396

African (AFR) AF: 0.0577 AC: 2396 AN: 41556

American (AMR) AF: 0.183 AC: 2796 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3466

East Asian (EAS) AF: 0.00581 AC: 30 AN: 5166

South Asian (SAS) AF: 0.0968 AC: 467 AN: 4826

European-Finnish (FIN) AF: 0.272 AC: 2885 AN: 10600

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16407 AN: 67950

Other (OTH) AF: 0.164 AC: 347 AN: 2114

Alfa AF: 0.144 Hom.: 415

Bravo AF: 0.161

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.33
DANN	Benign	0.76
PhyloP100		-1.5
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: rs34495634; hg19: chr21-47409580; COSMIC: COSV62613515; COSMIC: COSV62613515;