chr1-21822690-G-C

Variant names:

• chr1-21822690-G-C
• rs1049644
• NM_005529.7:c.*626C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005529.7(HSPG2):​c.*626C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 166,772 control chromosomes in the GnomAD database, including 7,848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7272 hom., cov: 29)
  • Exomes 𝑓: 0.23 (576 hom.)
• Consequence: HSPG2 NM_005529.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.97
• Publications: 4 publications found

Genes affected

HSPG2 (HGNC:5273): (heparan sulfate proteoglycan 2) This gene encodes the perlecan protein, which consists of a core protein to which three long chains of glycosaminoglycans (heparan sulfate or chondroitin sulfate) are attached. The perlecan protein is a large multidomain proteoglycan that binds to and cross-links many extracellular matrix components and cell-surface molecules. It has been shown that this protein interacts with laminin, prolargin, collagen type IV, FGFBP1, FBLN2, FGF7 and transthyretin, etc., and it plays essential roles in multiple biological activities. Perlecan is a key component of the vascular extracellular matrix, where it helps to maintain the endothelial barrier function. It is a potent inhibitor of smooth muscle cell proliferation and is thus thought to help maintain vascular homeostasis. It can also promote growth factor (e.g., FGF2) activity and thus stimulate endothelial growth and re-generation. It is a major component of basement membranes, where it is involved in the stabilization of other molecules as well as being involved with glomerular permeability to macromolecules and cell adhesion. Mutations in this gene cause Schwartz-Jampel syndrome type 1, Silverman-Handmaker type of dyssegmental dysplasia, and tardive dyskinesia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-21822690-G-C is Benign according to our data. Variant chr1-21822690-G-C is described in ClinVar as Benign. ClinVar VariationId is 295685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005529.7. 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
	HSPG2	NM_005529.7	MANE Select	c.*626C>G		3_prime_UTR	Exon 97 of 97	NP_005520.4
	LDLRAD2	NM_001013693.3	MANE Select	c.*475G>C		3_prime_UTR	Exon 5 of 5	NP_001013715.2	Q5SZI1
	HSPG2	NM_001291860.2		c.*626C>G		3_prime_UTR	Exon 97 of 97	NP_001278789.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPG2	ENST00000374695.8	TSL:1 MANE Select	c.*626C>G		3_prime_UTR	Exon 97 of 97	ENSP00000363827.3	P98160
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.*475G>C		3_prime_UTR	Exon 5 of 5	ENSP00000340988.2	Q5SZI1
	LDLRAD2	ENST00000543870.1	TSL:1	c.*218+257G>C		intron	N/A	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45349 AN: 151464 Hom.: 7246 Cov.: 29

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.167

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.283

GnomAD4 exome AF: 0.226 AC: 3439 AN: 15190 Hom.: 576 Cov.: 0 AF XY: 0.230 AC XY: 1881 AN XY: 8164

African (AFR) AF: 0.373 AC: 162 AN: 434

American (AMR) AF: 0.164 AC: 327 AN: 1988

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 72 AN: 268

East Asian (EAS) AF: 0.137 AC: 95 AN: 694

South Asian (SAS) AF: 0.332 AC: 459 AN: 1384

European-Finnish (FIN) AF: 0.269 AC: 112 AN: 416

Middle Eastern (MID) AF: 0.114 AC: 5 AN: 44

European-Non Finnish (NFE) AF: 0.220 AC: 2029 AN: 9240

Other (OTH) AF: 0.247 AC: 178 AN: 722

GnomAD4 genome AF: 0.300 AC: 45424 AN: 151582 Hom.: 7272 Cov.: 29 AF XY: 0.299 AC XY: 22167 AN XY: 74046

African (AFR) AF: 0.407 AC: 16785 AN: 41220

American (AMR) AF: 0.219 AC: 3346 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.302 AC: 1049 AN: 3470

East Asian (EAS) AF: 0.167 AC: 857 AN: 5126

South Asian (SAS) AF: 0.402 AC: 1927 AN: 4788

European-Finnish (FIN) AF: 0.313 AC: 3298 AN: 10532

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.255 AC: 17293 AN: 67898

Other (OTH) AF: 0.284 AC: 596 AN: 2100

Alfa AF: 0.150 Hom.: 294

Bravo AF: 0.294

Asia WGS AF: 0.305 AC: 1060 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Lethal Kniest-like syndrome (1)
-	-	1	not provided (1)
-	-	1	Schwartz-Jampel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.72
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs1049644; hg19: chr1-22149183; COSMIC: COSV60827857; COSMIC: COSV60827857;