rs563606558

Variant names:

• chr2-189179604-T-A
• NM_000393.5:c.1A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189179604-T-A
• chr2-189179604-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PVS1_Supporting PM2 BS1

The NM_000393.5(COL5A2):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL5A2 NM_000393.5 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.455

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 Likely_benign. Variant got -1 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 2 codons. Genomic position: 189179601. Lost 0.001 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000138 (2/1449812) while in subpopulation AFR AF= 0.00006 (2/33338). AF 95% confidence interval is 0.00000994. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.-42+45544A>T		intron_variant	Intron 4 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.-42+45544A>T		intron_variant	Intron 6 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.-42+45544A>T		intron_variant	Intron 5 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.-630A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 47	5		ENSP00000482184.1
COL5A2	ENST00000618828.1	c.-630A>T		5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000482184.1
COL5A2	ENST00000649966.1	c.-42+45544A>T		intron_variant	Intron 1 of 10			ENSP00000496785.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449812 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 720054

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.64	T
PROVEAN	Benign	-0.20	N;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.0	B;B
Vest4		0.74
MutPred		0.98		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.97
ClinPred		0.93	D
GERP RS		2.5
Varity_R		0.76
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-190044330;