rs3746995

Variant names:

• chr21-46124627-C-A
• rs3746995
• NM_001849.4:c.1672-24C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46124627-C-A
• chr21-46124627-C-G
• chr21-46124627-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001849.4(COL6A2):​c.1672-24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,611,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.789
• Publications: 9 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, 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: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1672-24C>A		intron_variant	Intron 21 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1672-24C>A		intron_variant	Intron 21 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1672-24C>A		intron_variant	Intron 21 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1672-24C>A		intron_variant	Intron 21 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1672-24C>A		intron_variant	Intron 21 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1672-24C>A		intron_variant	Intron 20 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.295-24C>A		intron_variant	Intron 6 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151850 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000317 AC: 79 AN: 249358 AF XY: 0.000340

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000214 AC: 313 AN: 1459954 Hom.: 0 Cov.: 36 AF XY: 0.000222 AC XY: 161 AN XY: 726340

African (AFR) AF: 0.000179 AC: 6 AN: 33464

American (AMR) AF: 0.000179 AC: 8 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 113 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111292

Other (OTH) AF: 0.000530 AC: 32 AN: 60344

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74266

African (AFR) AF: 0.000193 AC: 8 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000295 AC: 20 AN: 67880

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000402 Hom.: 2163

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.79
BranchPoint Hunter		4.0

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

Other links and lift over

dbSNP: rs3746995; hg19: chr21-47544541;