chr21-46132419-T-C

Position:

• chr21-46132419-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000300527.9(COL6A2):​c.2927T>C​(p.Leu976Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,607,566 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L976L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: COL6A2 ENST00000300527.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.82

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17084661).
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2927T>C	p.Leu976Ser	missense_variant	28/28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2927T>C	p.Leu976Ser	missense_variant	28/28	1	NM_001849.4	ENSP00000300527	P1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152220 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000213 AC: 52 AN: 244680 Hom.: 0 AF XY: 0.000195 AC XY: 26 AN XY: 133328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00121

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000154

Gnomad NFE exome AF: 0.000209

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000221 AC: 322 AN: 1455228 Hom.: 2 Cov.: 35 AF XY: 0.000210 AC XY: 152 AN XY: 723434

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00339

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000280

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152338 Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 17 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 08, 2023	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 21, 2017

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.010
Eigen_PC	Benign	0.075
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.057	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.89	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.63
Sift	Benign	0.061	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.21	B
Vest4		0.36
MVP		0.97
MPC		0.49
ClinPred		0.098	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.94

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: rs200200671; hg19: chr21-47552333;