NM_001849.4:c.-27-89G>A

Variant names:

• chr21-46111361-G-A
• rs115342490
• NM_001849.4:c.-27-89G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.-27-89G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 713,700 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (53 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (24 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.77
• Publications: 0 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

LOC124905043 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-46111361-G-A is Benign according to our data. Variant chr21-46111361-G-A is described in ClinVar as [Benign]. Clinvar id is 679820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0152 (2321/152314) while in subpopulation AFR AF = 0.0499 (2074/41572). AF 95% confidence interval is 0.0481. There are 53 homozygotes in GnomAd4. There are 1113 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.-27-89G>A		intron_variant	Intron 1 of 27	ENST00000300527.9	NP_001840.3
LOC124905043	XR_007067910.1	n.671C>T		non_coding_transcript_exon_variant	Exon 1 of 2
COL6A2	NM_058174.3	c.-27-89G>A		intron_variant	Intron 1 of 27		NP_478054.2
COL6A2	NM_058175.3	c.-27-89G>A		intron_variant	Intron 1 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.-27-89G>A		intron_variant	Intron 1 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.-27-89G>A		intron_variant	Intron 1 of 27	5		ENSP00000380870.1
COL6A2	ENST00000436769.5	c.-27-89G>A		intron_variant	Intron 1 of 2	2		ENSP00000390418.1
COL6A2	ENST00000409416.6	c.-116G>A		upstream_gene_variant		5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2318 AN: 152196 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00244 AC: 1369 AN: 561386 Hom.: 24 AF XY: 0.00208 AC XY: 613 AN XY: 295350

African (AFR) AF: 0.0469 AC: 738 AN: 15746

American (AMR) AF: 0.00426 AC: 130 AN: 30500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17042

East Asian (EAS) AF: 0.00536 AC: 170 AN: 31726

South Asian (SAS) AF: 0.000371 AC: 21 AN: 56574

European-Finnish (FIN) AF: 0.0000254 AC: 1 AN: 39328

Middle Eastern (MID) AF: 0.00381 AC: 9 AN: 2360

European-Non Finnish (NFE) AF: 0.000387 AC: 131 AN: 338324

Other (OTH) AF: 0.00567 AC: 169 AN: 29786

GnomAD4 genome AF: 0.0152 AC: 2321 AN: 152314 Hom.: 53 Cov.: 31 AF XY: 0.0149 AC XY: 1113 AN XY: 74472

African (AFR) AF: 0.0499 AC: 2074 AN: 41572

American (AMR) AF: 0.00954 AC: 146 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00850 AC: 44 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0145 Hom.: 3

Bravo AF: 0.0180

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.62
PhyloP100		-3.8
PromoterAI		0.0072	Neutral
Mutation Taster		=100/0	polymorphism

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: rs115342490; hg19: chr21-47531275; COSMIC: COSV100153131; COSMIC: COSV100153131;