2-189057323-G-T

Variant names:

• chr2-189057323-G-T
• rs138457003
• NM_000393.5:c.2334C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000393.5(COL5A2):​c.2334C>A​(p.Asp778Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D778D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.768
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25471544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2334C>A	p.Asp778Glu	missense_variant	Exon 34 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2196C>A	p.Asp732Glu	missense_variant	Exon 37 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.2196C>A	p.Asp732Glu	missense_variant	Exon 39 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.2196C>A	p.Asp732Glu	missense_variant	Exon 38 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2334C>A	p.Asp778Glu	missense_variant	Exon 34 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.1173C>A	p.Asp391Glu	missense_variant	Exon 27 of 47	5		ENSP00000482184.1
COL5A2	ENST00000470524.2	n.440C>A		non_coding_transcript_exon_variant	Exon 7 of 8	5

Frequencies

GnomAD3 genomes AF: 0.0000226 AC: 3 AN: 132972 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000465

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000547 AC: 518 AN: 946484 Hom.: 0 Cov.: 27 AF XY: 0.000535 AC XY: 261 AN XY: 488062

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000171 AC: 4 AN: 23382

American (AMR) AF: 0.0000234 AC: 1 AN: 42734

Ashkenazi Jewish (ASJ) AF: 0.0000934 AC: 2 AN: 21412

East Asian (EAS) AF: 0.0000594 AC: 2 AN: 33664

South Asian (SAS) AF: 0.000118 AC: 9 AN: 76430

European-Finnish (FIN) AF: 0.0000421 AC: 2 AN: 47458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 0.000734 AC: 481 AN: 655740

Other (OTH) AF: 0.000408 AC: 17 AN: 41644

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000226 AC: 3 AN: 132980 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 1 AN XY: 63206

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 35912

American (AMR) AF: 0.00 AC: 0 AN: 12702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3294

East Asian (EAS) AF: 0.000466 AC: 2 AN: 4292

South Asian (SAS) AF: 0.00 AC: 0 AN: 4012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.0000157 AC: 1 AN: 63614

Other (OTH) AF: 0.00 AC: 0 AN: 1802

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;D;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	-0.060	N;.;N
PhyloP100		0.77
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.22	N;.;.
REVEL	Benign	0.29
Sift	Benign	0.81	T;.;.
Sift4G	Benign	1.0	T;T;.
Polyphen		0.36	B;.;B
Vest4		0.29
MutPred		0.25		Loss of methylation at R779 (P = 0.1796);.;Loss of methylation at R779 (P = 0.1796);
MVP		0.60
MPC		0.24
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.053
gMVP		0.17
Mutation Taster		=90/10	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: rs138457003; hg19: chr2-189922049; COSMIC: COSV66415185;