rs11702055

Positions:

• chr21-45990416-C-T
• chr21-45990416-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001848.3(COL6A1):​c.996C>T​(p.Gly332Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,068,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.08

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 21-45990416-C-T is Benign according to our data. Variant chr21-45990416-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282660.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.996C>T	p.Gly332Gly	synonymous_variant	13/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.996C>T	p.Gly332Gly	synonymous_variant	13/35	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.000739 AC: 10 AN: 13534 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00168

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000982

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000375 AC: 73 AN: 194822 Hom.: 0 AF XY: 0.000398 AC XY: 43 AN XY: 108078

Gnomad AFR exome AF: 0.0000928

Gnomad AMR exome AF: 0.000813

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000568

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 142 AN: 1055220 Hom.: 0 Cov.: 49 AF XY: 0.000146 AC XY: 75 AN XY: 515326

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.000832

Gnomad4 ASJ exome AF: 0.0000731

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000625

Gnomad4 FIN exome AF: 0.0000412

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.0000815

GnomAD4 genome AF: 0.000737 AC: 10 AN: 13560 Hom.: 0 Cov.: 0 AF XY: 0.000775 AC XY: 5 AN XY: 6448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00166

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00168

Gnomad4 NFE AF: 0.000981

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000562 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	COL6A1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2017	The c.996 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.996 C>T variant is observed in 18/23704 (0.1%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016). Several splice prediction algorithms are inconsistent in their predictions as to whether or not the c.996C>T alteration damages the natural donor site in intron 13 or introduces a cryptic donor site in exon 13. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2017	- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11702055; hg19: chr21-47410330; COSMIC: COSV62612544; COSMIC: COSV62612544;