21-46125455-AC-ACCC

Variant names:

• chr21-46125455-A-ACC
• rs149954350
• NM_001849.4:c.1817-4_1817-3dupCC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PVS1_Moderate BP6_Very_Strong BS2

The NM_001849.4(COL6A2):​c.1817-4_1817-3dupCC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,610,310 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: COL6A2 NM_001849.4 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.481

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 Benign. Variant got -10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.8, offset of 0 (no position change), new splice context is: accctgccacccccccccAGact. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 21-46125455-A-ACC is Benign according to our data. Variant chr21-46125455-A-ACC is described in ClinVar as [Likely_benign]. Clinvar id is 290341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1817-4_1817-3dupCC		splice_acceptor_variant, intron_variant	Intron 24 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1817-4_1817-3dupCC		splice_acceptor_variant, intron_variant	Intron 24 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1817-4_1817-3dupCC		splice_acceptor_variant, intron_variant	Intron 24 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1817-4_1817-3dupCC		splice_acceptor_variant, intron_variant	Intron 24 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000413758.1	c.484_485dupCC	p.Asp163GlnfsTer88	frameshift_variant	Exon 10 of 11	3		ENSP00000395751.1
COL6A2	ENST00000397763.6	c.1817-4_1817-3dupCC		splice_acceptor_variant, intron_variant	Intron 24 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1817-4_1817-3dupCC		splice_acceptor_variant, intron_variant	Intron 23 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151700 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000305 AC: 76 AN: 249506 Hom.: 1 AF XY: 0.000354 AC XY: 48 AN XY: 135402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00136

Gnomad SAS exome AF: 0.000883

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000178 AC: 260 AN: 1458492 Hom.: 3 Cov.: 52 AF XY: 0.000211 AC XY: 153 AN XY: 725568

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000706

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151818 Hom.: 0 Cov.: 30 AF XY: 0.0000809 AC XY: 6 AN XY: 74198

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000586

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Sep 05, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myosclerosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Collagen 6-related myopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bethlem myopathy 1A Benign:1

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs149954350; hg19: chr21-47545369;