21-46111498-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001849.4(COL6A2):c.22G>A(p.Val8Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,612,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.0490

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]

LOC124905043 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017417401).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.22G>A	p.Val8Met	missense_variant	2/28	ENST00000300527.9
COL6A2	NM_058174.3	c.22G>A	p.Val8Met	missense_variant	2/28	ENST00000397763.6
LOC124905043	XR_007067910.1	n.534C>T		non_coding_transcript_exon_variant	1/2
COL6A2	NM_058175.3	c.22G>A	p.Val8Met	missense_variant	2/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.22G>A	p.Val8Met	missense_variant	2/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.22G>A	p.Val8Met	missense_variant	2/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.22G>A	p.Val8Met	missense_variant	1/27	5
COL6A2	ENST00000436769.5	c.22G>A	p.Val8Met	missense_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000473 AC: 118 AN: 249296 Hom.: 0 AF XY: 0.000325 AC XY: 44 AN XY: 135430

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1460360 Hom.: 0 Cov.: 31 AF XY: 0.000131 AC XY: 95 AN XY: 726404

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000238

ExAC AF: 0.000528 AC: 64

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30564623) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2016	- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	11
Dann	Benign	0.95
DEOGEN2	Benign	0.20	T;.;T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.64	T;T;T;.;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.51	N;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.043	D;D;D;D;D
Sift4G	Benign	0.094	T;T;T;T;T
Polyphen		0.0080	B;P;.;P;D
Vest4		0.12
MVP		0.81
MPC		0.14
ClinPred		0.0098	T
GERP RS		1.2
Varity_R		0.036
gMVP		0.23

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: rs192476178; hg19: chr21-47531412; COSMIC: COSV56006597; COSMIC: COSV56006597;