rs78764604

Variant names:

• chr21-46125762-G-C
• rs78764604
• NM_001849.4:c.1970-23G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-46125762-G-C
• chr21-46125762-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.1970-23G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 1,608,478 control chromosomes in the GnomAD database, including 6,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (354 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5854 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.20
• Publications: 3 publications found

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]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, SD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-46125762-G-C is Benign according to our data. Variant chr21-46125762-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.1970-23G>C		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1970-23G>C		intron	N/A	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1970-23G>C		intron	N/A	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1970-23G>C		intron	N/A	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1970-23G>C		intron	N/A	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.2165-23G>C		intron	N/A	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8512 AN: 152170 Hom.: 354 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0580

GnomAD2 exomes AF: 0.0556 AC: 13607 AN: 244564 AF XY: 0.0567

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0309

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.00115

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0907

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0828 AC: 120611 AN: 1456190 Hom.: 5854 Cov.: 37 AF XY: 0.0808 AC XY: 58451 AN XY: 723586

African (AFR) AF: 0.0135 AC: 452 AN: 33392

American (AMR) AF: 0.0329 AC: 1464 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.0774 AC: 2017 AN: 26076

East Asian (EAS) AF: 0.00106 AC: 42 AN: 39570

South Asian (SAS) AF: 0.0151 AC: 1302 AN: 86066

European-Finnish (FIN) AF: 0.0387 AC: 2011 AN: 51950

Middle Eastern (MID) AF: 0.0402 AC: 232 AN: 5764

European-Non Finnish (NFE) AF: 0.0979 AC: 108510 AN: 1108664

Other (OTH) AF: 0.0762 AC: 4581 AN: 60156

GnomAD4 genome AF: 0.0559 AC: 8512 AN: 152288 Hom.: 354 Cov.: 33 AF XY: 0.0527 AC XY: 3922 AN XY: 74468

African (AFR) AF: 0.0179 AC: 743 AN: 41574

American (AMR) AF: 0.0471 AC: 720 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 251 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4828

European-Finnish (FIN) AF: 0.0339 AC: 360 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0919 AC: 6249 AN: 68008

Other (OTH) AF: 0.0573 AC: 121 AN: 2110

Alfa AF: 0.0412 Hom.: 44

Bravo AF: 0.0558

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.022
DANN	Benign	0.57
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78764604; hg19: chr21-47545676;