rs201720941

Variant names:

• chr2-189043275-G-A
• rs201720941
• NM_000393.5:c.3364-17C>T

Variant summary

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

The NM_000393.5(COL5A2):​c.3364-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,565,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (3 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0960
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-189043275-G-A is Benign according to our data. Variant chr2-189043275-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136950.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 = 0.000704 (107/152004) while in subpopulation AMR AF = 0.00164 (25/15274). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 107 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.3364-17C>T		intron	N/A	NP_000384.2	P05997

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.3364-17C>T		intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.3361-17C>T		intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.3256-17C>T		intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.000704 AC: 107 AN: 151886 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000876 AC: 218 AN: 248758 AF XY: 0.000975

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00271

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000909

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000598 AC: 845 AN: 1413114 Hom.: 3 Cov.: 23 AF XY: 0.000643 AC XY: 454 AN XY: 705848

African (AFR) AF: 0.000552 AC: 18 AN: 32612

American (AMR) AF: 0.00155 AC: 69 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 75 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.000917 AC: 78 AN: 85074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.0115 AC: 65 AN: 5664

European-Non Finnish (NFE) AF: 0.000421 AC: 450 AN: 1068010

Other (OTH) AF: 0.00153 AC: 90 AN: 58698

GnomAD4 genome AF: 0.000704 AC: 107 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.000673 AC XY: 50 AN XY: 74296

African (AFR) AF: 0.000145 AC: 6 AN: 41446

American (AMR) AF: 0.00164 AC: 25 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 67974

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000842

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.29
PhyloP100		0.096
Mutation Taster		=100/0	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: rs201720941; hg19: chr2-189908001;