Genetic Variant NM_001848.3:c.1475C>G (chr21-45997713-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001848.3(COL6A1):c.1475C>G(p.Ala492Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A492V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.196

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20035473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.1475C>G	p.Ala492Gly	missense_variant	Exon 22 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.1475C>G	p.Ala492Gly	missense_variant	Exon 22 of 35	1	NM_001848.3	ENSP00000355180.3		P12109
COL6A1	ENST00000683550.1 link	n.250C>G		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440676

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33072

American (AMR)

AF:

0.00

AC:

AN:

42182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

38710

South Asian (SAS)

AF:

0.00

AC:

AN:

83112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101764

Other (OTH)

AF:

0.00

AC:

AN:

59546

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

0.095

BayesDel_addAF

Benign

0.00024

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.52

D;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.88

D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.7

L;.

PhyloP100

-0.20

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.96

N;.

REVEL

Benign

0.17

Sift

Benign

0.37

T;.

Sift4G

Benign

0.37

T;T

Polyphen

0.22

B;.

Vest4

0.31

MutPred

0.42

Loss of stability (P = 0.1196);Loss of stability (P = 0.1196);

MVP

0.45

MPC

0.73

ClinPred

0.35

GERP RS

3.4

Varity_R

0.23

gMVP

0.31

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over