Genetic Variant COL6A1:p.Thr208Arg (chr21-45986978-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001848.3(COL6A1):c.623C>G(p.Thr208Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,980 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T208M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.713

Publications

0 publications found

Variant links:

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):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Bethlem myopathy 1A
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.623C>G	p.Thr208Arg	missense_variant	Exon 5 of 35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.623C>G	p.Thr208Arg	missense_variant	Exon 5 of 35	1	NM_001848.3	ENSP00000355180.3		P12109
COL6A1	ENST00000492851.1 link	n.-131C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399980

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31930

American (AMR)

AF:

0.00

AC:

AN:

36446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25208

East Asian (EAS)

AF:

0.00

AC:

AN:

36262

South Asian (SAS)

AF:

0.00

AC:

AN:

79660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1081446

Other (OTH)

AF:

0.00

AC:

AN:

58138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

0.049

Eigen_PC

Benign

0.0072

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.73

T;T

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.0

L;.

PhyloP100

0.71

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.41

Sift

Benign

0.23

T;.

Sift4G

Benign

0.33

T;T

Polyphen

1.0

D;.

Vest4

0.49

MutPred

0.56

Gain of methylation at T208 (P = 0.0335);Gain of methylation at T208 (P = 0.0335);

MVP

0.61

MPC

0.25

ClinPred

0.91

GERP RS

4.2

Varity_R

0.27

gMVP

0.57

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.48

Position offset: 1

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

Publications

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21-45986978-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over