rs78905646

Positions:

• chr2-189034121-G-A
• chr2-189034121-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000393.5(COL5A2):​c.4449C>T​(p.Gly1483=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,862 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1483G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 32)
  • Exomes 𝑓: 0.022 (415 hom.)
• Consequence: COL5A2 NM_000393.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.632

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-189034121-G-A is Benign according to our data. Variant chr2-189034121-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189034121-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.632 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0158 (2403/152166) while in subpopulation NFE AF= 0.0207 (1408/67990). AF 95% confidence interval is 0.0198. There are 26 homozygotes in gnomad4. There are 1190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2403 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.4449C>T	p.Gly1483=	synonymous_variant	54/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.4311C>T	p.Gly1437=	synonymous_variant	57/57
COL5A2	XM_047443251.1	c.4311C>T	p.Gly1437=	synonymous_variant	59/59
COL5A2	XM_047443252.1	c.4311C>T	p.Gly1437=	synonymous_variant	58/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.4449C>T	p.Gly1483=	synonymous_variant	54/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.3288C>T	p.Gly1096=	synonymous_variant	47/47	5

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2404 AN: 152048 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0175 AC: 4398 AN: 251166 Hom.: 69 AF XY: 0.0181 AC XY: 2450 AN XY: 135726

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.000599

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0326

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0217 AC: 31755 AN: 1461696 Hom.: 415 Cov.: 31 AF XY: 0.0216 AC XY: 15683 AN XY: 727146

Gnomad4 AFR exome AF: 0.00332

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.00574

Gnomad4 SAS exome AF: 0.0143

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0235

Gnomad4 OTH exome AF: 0.0196

GnomAD4 genome AF: 0.0158 AC: 2403 AN: 152166 Hom.: 26 Cov.: 32 AF XY: 0.0160 AC XY: 1190 AN XY: 74380

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.0145

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0188 Hom.: 12

Bravo AF: 0.0145

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0226

EpiControl AF: 0.0208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

Ehlers-Danlos syndrome type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.4
DANN	Benign	0.61

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: rs78905646; hg19: chr2-189898847;