chr21-46002046-T-C

Variant names:

• chr21-46002046-T-C
• rs138884734
• NM_001848.3:c.2042T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):​c.2042T>C​(p.Ile681Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00278 in 1,612,250 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I681V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (41 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.03
• 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 (MetaRNN=0.005509138).
• BP6: Variant 21-46002046-T-C is Benign according to our data. Variant chr21-46002046-T-C is described in ClinVar as Benign. ClinVar VariationId is 93844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1814/152240) while in subpopulation AFR AF = 0.0391 (1624/41540). AF 95% confidence interval is 0.0375. There are 28 homozygotes in GnomAd4. There are 857 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.2042T>C	p.Ile681Thr	missense	Exon 31 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.2042T>C	p.Ile681Thr	missense	Exon 31 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000498614.5	TSL:1	n.276T>C		non_coding_transcript_exon	Exon 2 of 6
	COL6A1	ENST00000612273.2	TSL:5	c.167T>C	p.Ile56Thr	missense	Exon 2 of 7	ENSP00000483630.2	A0A087X0S5

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1810 AN: 152122 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00382 AC: 929 AN: 243370 AF XY: 0.00326

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000482

Gnomad OTH exome AF: 0.00369

GnomAD4 exome AF: 0.00183 AC: 2674 AN: 1460010 Hom.: 41 Cov.: 35 AF XY: 0.00172 AC XY: 1251 AN XY: 726284

African (AFR) AF: 0.0396 AC: 1324 AN: 33472

American (AMR) AF: 0.00226 AC: 101 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 592 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52202

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5736

European-Non Finnish (NFE) AF: 0.000330 AC: 367 AN: 1111774

Other (OTH) AF: 0.00452 AC: 273 AN: 60342

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152240 Hom.: 28 Cov.: 33 AF XY: 0.0115 AC XY: 857 AN XY: 74442

African (AFR) AF: 0.0391 AC: 1624 AN: 41540

American (AMR) AF: 0.00340 AC: 52 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67996

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00372 Hom.: 23

Bravo AF: 0.0128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0393 AC: 173

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00425 AC: 516

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000772

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.51	P
Vest4		0.59
MVP		0.39
MPC		0.94
ClinPred		0.025	T
GERP RS		4.6
Varity_R		0.45
gMVP		0.45
Mutation Taster		=92/8	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: rs138884734; hg19: chr21-47421960; COSMIC: COSV106530305; COSMIC: COSV106530305;