rs138884734

chr21-46002046-T-Cchr21-46002046-T-A

Variant summary

Our verdict is Benign. Variant got -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:8
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 93844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46002046-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2042T>C	p.Ile681Thr	missense_variant	31/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2042T>C	p.Ile681Thr	missense_variant	31/35	1	NM_001848.3	P1

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

GnomAD3 exomes AF: 0.00382 AC: 929 AN: 243370 Hom.: 13 AF XY: 0.00326 AC XY: 431 AN XY: 132276

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 SAS exome AF: 0.0000330

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

Gnomad4 AFR exome AF: 0.0396

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.00452

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

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00329 Hom.: 7

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2012	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Nov 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.0013
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;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

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

LitVar

Other links and lift over

dbSNP: rs138884734; hg19: chr21-47421960;