NM_001848.3:c.1518T>C

Variant names:

• chr21-45997756-T-C
• rs35134265
• NM_001848.3:c.1518T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001848.3(COL6A1):​c.1518T>C​(p.Gly506Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000585 in 1,590,020 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.67
• Publications: 1 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, AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-45997756-T-C is Benign according to our data. Variant chr21-45997756-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00302 (458/151720) while in subpopulation AFR AF = 0.0106 (439/41382). AF 95% confidence interval is 0.00979. There are 3 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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.1518T>C	p.Gly506Gly	synonymous	Exon 22 of 35	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.1518T>C	p.Gly506Gly	synonymous	Exon 22 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.565-4771T>C		intron	N/A	ENSP00000536193.1
	COL6A1	ENST00000683550.1		n.293T>C		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 456 AN: 151600 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000753 AC: 156 AN: 207064 AF XY: 0.000510

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000618

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000634

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000559

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000328 AC: 472 AN: 1438300 Hom.: 2 Cov.: 34 AF XY: 0.000278 AC XY: 198 AN XY: 713346

African (AFR) AF: 0.0107 AC: 353 AN: 33034

American (AMR) AF: 0.000668 AC: 28 AN: 41902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25700

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38600

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50736

Middle Eastern (MID) AF: 0.000943 AC: 5 AN: 5304

European-Non Finnish (NFE) AF: 0.0000336 AC: 37 AN: 1100728

Other (OTH) AF: 0.000791 AC: 47 AN: 59414

GnomAD4 genome AF: 0.00302 AC: 458 AN: 151720 Hom.: 3 Cov.: 34 AF XY: 0.00282 AC XY: 209 AN XY: 74164

African (AFR) AF: 0.0106 AC: 439 AN: 41382

American (AMR) AF: 0.000524 AC: 8 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67832

Other (OTH) AF: 0.00190 AC: 4 AN: 2102

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.00370

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.067
DANN	Benign	0.34
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism

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: rs35134265; hg19: chr21-47417670;