2-189110428-G-T

Variant names:

• chr2-189110428-G-T
• rs758092388
• NM_000393.5:c.119C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BS1 BS2

The NM_000393.5(COL5A2):​c.119C>A​(p.Ala40Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.61
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28366753).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000547 (8/1461432) while in subpopulation SAS AF = 0.0000928 (8/86244). AF 95% confidence interval is 0.0000458. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.119C>A	p.Ala40Asp	missense_variant	Exon 2 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.-20C>A		5_prime_UTR_variant	Exon 5 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.-20C>A		5_prime_UTR_variant	Exon 7 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.-20C>A		5_prime_UTR_variant	Exon 6 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.119C>A	p.Ala40Asp	missense_variant	Exon 2 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.-512C>A		5_prime_UTR_variant	Exon 2 of 47	5		ENSP00000482184.1
COL5A2	ENST00000649966.1	c.-20C>A		5_prime_UTR_variant	Exon 2 of 11			ENSP00000496785.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251200 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461432 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727068

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111616

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.027
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.77	N;N
PhyloP100		3.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.13
Sift	Benign	0.16	T;.
Sift4G	Uncertain	0.054	T;.
Polyphen		0.0010	B;B
Vest4		0.26
MutPred		0.56		Gain of disorder (P = 0.0326);Gain of disorder (P = 0.0326);
MVP		0.17
MPC		1.0
ClinPred		0.49	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.68
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758092388; hg19: chr2-189975154;