rs113169531

Positions:

• chr21-46132509-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001849.4(COL6A2):​c.3017C>T​(p.Ala1006Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,607,008 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1006T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.481

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006705165).
• BP6: Variant 21-46132509-C-T is Benign according to our data. Variant chr21-46132509-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 284831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.3017C>T	p.Ala1006Val	missense_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.3017C>T	p.Ala1006Val	missense_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 255 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000490 AC: 116 AN: 236846 Hom.: 0 AF XY: 0.000339 AC XY: 44 AN XY: 129754

Gnomad AFR exome AF: 0.00470

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000512

Gnomad EAS exome AF: 0.000881

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000853

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.000268 AC: 390 AN: 1454638 Hom.: 3 Cov.: 34 AF XY: 0.000247 AC XY: 179 AN XY: 723858

Gnomad4 AFR exome AF: 0.00607

Gnomad4 AMR exome AF: 0.000359

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000211

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.000746

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152370 Hom.: 0 Cov.: 34 AF XY: 0.00136 AC XY: 101 AN XY: 74502

Gnomad4 AFR AF: 0.00546

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000401 Hom.: 0

Bravo AF: 0.00181

ESP6500AA AF: 0.00455 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000504 AC: 61

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2015	- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 19, 2017

- -

COL6A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.0
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.41	N
REVEL	Benign	0.081
Sift	Benign	0.60	T
Sift4G	Benign	0.37	T
Polyphen		0.056	B
Vest4		0.083
MVP		0.73
MPC		0.14
ClinPred		0.0014	T
GERP RS		1.4
Varity_R		0.029
gMVP		0.75

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: rs113169531; hg19: chr21-47552423; COSMIC: COSV99385027; COSMIC: COSV99385027;