rs138401567

Variant names:

• chr21-45990401-C-T
• rs138401567
• NM_001848.3:c.981C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-45990401-C-T
• chr21-45990401-C-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001848.3(COL6A1):​c.981C>T​(p.Ile327Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,371,302 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.29
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 21-45990401-C-T is Benign according to our data. Variant chr21-45990401-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000674 (74/109736) while in subpopulation AMR AF = 0.00134 (13/9678). AF 95% confidence interval is 0.000795. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

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.981C>T	p.Ile327Ile	synonymous	Exon 13 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.981C>T	p.Ile327Ile	synonymous	Exon 13 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.564+3740C>T		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.000666 AC: 73 AN: 109616 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.000643

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000863

Gnomad OTH AF: 0.000683

GnomAD2 exomes AF: 0.000730 AC: 162 AN: 221830 AF XY: 0.000709

Gnomad AFR exome AF: 0.000576

Gnomad AMR exome AF: 0.000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000287

Gnomad FIN exome AF: 0.000476

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00124 AC: 1559 AN: 1261566 Hom.: 1 Cov.: 49 AF XY: 0.00120 AC XY: 748 AN XY: 625088

African (AFR) AF: 0.000351 AC: 10 AN: 28484

American (AMR) AF: 0.000938 AC: 36 AN: 38390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19182

East Asian (EAS) AF: 0.0000932 AC: 2 AN: 21464

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79976

European-Finnish (FIN) AF: 0.000653 AC: 23 AN: 35198

Middle Eastern (MID) AF: 0.000427 AC: 2 AN: 4688

European-Non Finnish (NFE) AF: 0.00144 AC: 1421 AN: 986894

Other (OTH) AF: 0.00133 AC: 63 AN: 47290

GnomAD4 genome AF: 0.000674 AC: 74 AN: 109736 Hom.: 0 Cov.: 24 AF XY: 0.000478 AC XY: 25 AN XY: 52354

African (AFR) AF: 0.000310 AC: 10 AN: 32288

American (AMR) AF: 0.00134 AC: 13 AN: 9678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2542

East Asian (EAS) AF: 0.00 AC: 0 AN: 2988

South Asian (SAS) AF: 0.000377 AC: 1 AN: 2656

European-Finnish (FIN) AF: 0.000643 AC: 4 AN: 6222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.000863 AC: 44 AN: 51004

Other (OTH) AF: 0.00135 AC: 2 AN: 1486

Alfa AF: 0.000886 Hom.: 0

Bravo AF: 0.000616

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.88
PhyloP100		-1.3

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: rs138401567; hg19: chr21-47410315;