NM_000393.5:c.*1165G>A

Variant names:

• chr2-189032905-C-T
• rs13914
• NM_000393.5:c.*1165G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.*1165G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 152,508 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (201 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: COL5A2 NM_000393.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.55

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-189032905-C-T is Benign according to our data. Variant chr2-189032905-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189032905-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.*1165G>A		3_prime_UTR_variant	Exon 54 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.*1165G>A		3_prime_UTR_variant	Exon 57 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.*1165G>A		3_prime_UTR_variant	Exon 59 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.*1165G>A		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.*1165G>A		3_prime_UTR_variant	Exon 54 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828	c.*1165G>A		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.0466 AC: 7083 AN: 151956 Hom.: 203 Cov.: 32

Gnomad AFR AF: 0.0840

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.0734

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0304

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0265

Gnomad OTH AF: 0.0468

GnomAD4 exome AF: 0.0208 AC: 9 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.0269 AC XY: 7 AN XY: 260

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.0466 AC: 7086 AN: 152076 Hom.: 201 Cov.: 32 AF XY: 0.0469 AC XY: 3491 AN XY: 74356

Gnomad4 AFR AF: 0.0839

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0208

Gnomad4 EAS AF: 0.0739

Gnomad4 SAS AF: 0.0441

Gnomad4 FIN AF: 0.0304

Gnomad4 NFE AF: 0.0265

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0275 Hom.: 73

Bravo AF: 0.0498

Asia WGS AF: 0.0990 AC: 344 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 12, 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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.19

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: rs13914; hg19: chr2-189897631; COSMIC: COSV66411433;