NM_000393.5:c.*1400A>G

Variant names:

• chr2-189032670-T-C
• rs12886
• NM_000393.5:c.*1400A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000393.5(COL5A2):​c.*1400A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 152,350 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1 hom.)
• Consequence: COL5A2 NM_000393.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.698

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-189032670-T-C is Benign according to our data. Variant chr2-189032670-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 333107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2358/152082) while in subpopulation NFE AF= 0.0201 (1365/67944). AF 95% confidence interval is 0.0192. There are 24 homozygotes in gnomad4. There are 1169 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2358 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.*1400A>G		3_prime_UTR_variant	Exon 54 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.*1400A>G		3_prime_UTR_variant	Exon 57 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.*1400A>G		3_prime_UTR_variant	Exon 59 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.*1400A>G		3_prime_UTR_variant	Exon 58 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866	c.*1400A>G		3_prime_UTR_variant	Exon 54 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828	c.*1400A>G		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2361 AN: 151964 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0261 AC: 7 AN: 268 Hom.: 1 Cov.: 0 AF XY: 0.0235 AC XY: 4 AN XY: 170

Gnomad4 FIN exome AF: 0.0267

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0155 AC: 2358 AN: 152082 Hom.: 24 Cov.: 32 AF XY: 0.0157 AC XY: 1169 AN XY: 74376

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0323

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0167 Hom.: 5

Bravo AF: 0.0143

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome type 7A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs12886; hg19: chr2-189897396;