rs139229616

Variant names:

• chr2-189035029-C-T
• rs139229616
• NM_000393.5:c.4240G>A

Variant summary

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

The ENST00000374866.9(COL5A2):​c.4240G>A​(p.Asp1414Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,613,852 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1414G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: COL5A2 ENST00000374866.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.00
• Publications: 11 publications found

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]

COL5A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008553684).
• BP6: Variant 2-189035029-C-T is Benign according to our data. Variant chr2-189035029-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00111 (169/152174) while in subpopulation AMR AF = 0.00242 (37/15276). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 169 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000374866.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.4240G>A	p.Asp1414Asn	missense	Exon 53 of 54	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.4240G>A	p.Asp1414Asn	missense	Exon 53 of 54	ENSP00000364000.3
	COL5A2	ENST00000618828.1	TSL:5	c.3079G>A	p.Asp1027Asn	missense	Exon 46 of 47	ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00142 AC: 357 AN: 251200 AF XY: 0.00121

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00129 AC: 1885 AN: 1461678 Hom.: 6 Cov.: 33 AF XY: 0.00126 AC XY: 919 AN XY: 727146

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 425 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00113 AC: 1251 AN: 1111886

Other (OTH) AF: 0.00199 AC: 120 AN: 60386

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00112 AC XY: 83 AN XY: 74372

African (AFR) AF: 0.0000963 AC: 4 AN: 41532

American (AMR) AF: 0.00242 AC: 37 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67992

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00175 Hom.: 3

Bravo AF: 0.00132

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000988 AC: 120

EpiCase AF: 0.00109

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	COL5A2-related disorder (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.032	D
Sift4G	Benign	0.27	T
Polyphen		0.90	P
Vest4		0.34
MVP		0.76
MPC		0.25
ClinPred		0.022	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.39
Mutation Taster		=88/12	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: rs139229616; hg19: chr2-189899755; COSMIC: COSV66407247;