rs77745490

Variant names:

• chr21-46111342-G-C
• rs77745490
• NM_001849.4:c.-27-108G>C

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.-27-108G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 650,608 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (43 hom., cov: 31)
  • Exomes 𝑓: 0.020 (151 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.684

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]

LOC124905043 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-46111342-G-C is Benign according to our data. Variant chr21-46111342-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 677612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2538/152344) while in subpopulation NFE AF = 0.0294 (1998/68024). AF 95% confidence interval is 0.0283. There are 43 homozygotes in GnomAd4. There are 1112 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.-27-108G>C		intron_variant	Intron 1 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.-27-108G>C		intron_variant	Intron 1 of 27		NP_478054.2
COL6A2	NM_058175.3	c.-27-108G>C		intron_variant	Intron 1 of 27		NP_478055.2
LOC124905043	XR_007067910.1	n.690C>G		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.-27-108G>C		intron_variant	Intron 1 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.-27-108G>C		intron_variant	Intron 1 of 27	5		ENSP00000380870.1
COL6A2	ENST00000436769.5	c.-27-108G>C		intron_variant	Intron 1 of 2	2		ENSP00000390418.1
COL6A2	ENST00000409416.6	c.-135G>C		upstream_gene_variant		5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2538 AN: 152226 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00588

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0204 AC: 10147 AN: 498264 Hom.: 151 AF XY: 0.0199 AC XY: 5230 AN XY: 262626

African (AFR) AF: 0.00456 AC: 65 AN: 14256

American (AMR) AF: 0.00544 AC: 153 AN: 28140

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 224 AN: 15798

East Asian (EAS) AF: 0.00 AC: 0 AN: 31122

South Asian (SAS) AF: 0.00709 AC: 374 AN: 52736

European-Finnish (FIN) AF: 0.00937 AC: 331 AN: 35344

Middle Eastern (MID) AF: 0.00612 AC: 13 AN: 2124

European-Non Finnish (NFE) AF: 0.0291 AC: 8484 AN: 291126

Other (OTH) AF: 0.0182 AC: 503 AN: 27618

GnomAD4 genome AF: 0.0167 AC: 2538 AN: 152344 Hom.: 43 Cov.: 31 AF XY: 0.0149 AC XY: 1112 AN XY: 74500

African (AFR) AF: 0.00587 AC: 244 AN: 41586

American (AMR) AF: 0.00849 AC: 130 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00640 AC: 68 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0294 AC: 1998 AN: 68024

Other (OTH) AF: 0.0147 AC: 31 AN: 2112

Alfa AF: 0.0235 Hom.: 5

Bravo AF: 0.0159

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 16, 2018

GeneDx

Significance: Likely 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	-0.86
CADD	Benign	1.7
DANN	Benign	0.79
PhyloP100		-0.68
PromoterAI		0.033	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs77745490; hg19: chr21-47531256;