1-159713648-C-G

Variant names:

• chr1-159713648-C-G
• rs1800947
• NM_000567.3:c.552G>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001382703.1(CRP):​c.194-8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 1,614,146 control chromosomes in the GnomAD database, including 2,919 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.045 (225 hom., cov: 31)
  • Exomes 𝑓: 0.058 (2694 hom.)
• Consequence: CRP NM_001382703.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.446

Genes affected

CRP (HGNC:2367): (C-reactive protein) The protein encoded by this gene belongs to the pentraxin family which also includes serum amyloid P component protein and pentraxin 3. Pentraxins are involved in complement activation and amplification via communication with complement initiation pattern recognition molecules, but also complement regulation via recruitment of complement regulators. The encoded protein has a calcium dependent ligand binding domain with a distinctive flattened beta-jellyroll structure. It exists in two forms as either a pentamer in circulation or as a nonsoluble monomer in tissues. It is involved in several host defense related functions based on its ability to recognize foreign pathogens and damaged cells of the host and to initiate their elimination by interacting with humoral and cellular effector systems in the blood. Consequently, the level of this protein in plasma increases greatly during acute phase response to tissue injury, infection, or other inflammatory stimuli. Elevated expression of the encoded protein is associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRP	NM_000567.3	c.552G>C	p.Leu184Leu	synonymous_variant	Exon 2 of 2	ENST00000255030.9	NP_000558.2
CRP	NM_001329057.2	c.552G>C	p.Leu184Leu	synonymous_variant	Exon 2 of 3		NP_001315986.1
CRP	NM_001382703.1	c.194-8G>C		splice_region_variant, intron_variant	Intron 2 of 2		NP_001369632.1
CRP	NM_001329058.2	c.198-45G>C		intron_variant	Intron 2 of 3		NP_001315987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRP	ENST00000255030.9	c.552G>C	p.Leu184Leu	synonymous_variant	Exon 2 of 2	1	NM_000567.3	ENSP00000255030.5

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6839 AN: 152148 Hom.: 225 Cov.: 31

Gnomad AFR AF: 0.00997

Gnomad AMI AF: 0.0637

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.0671

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0566

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0569

GnomAD3 exomes AF: 0.0509 AC: 12798 AN: 251474 Hom.: 431 AF XY: 0.0512 AC XY: 6957 AN XY: 135914

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0827

Gnomad EAS exome AF: 0.0788

Gnomad SAS exome AF: 0.0208

Gnomad FIN exome AF: 0.0578

Gnomad NFE exome AF: 0.0647

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0577 AC: 84405 AN: 1461880 Hom.: 2694 Cov.: 31 AF XY: 0.0572 AC XY: 41575 AN XY: 727242

Gnomad4 AFR exome AF: 0.00893

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0805

Gnomad4 EAS exome AF: 0.0504

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.0601

Gnomad4 NFE exome AF: 0.0633

Gnomad4 OTH exome AF: 0.0558

GnomAD4 genome AF: 0.0449 AC: 6832 AN: 152266 Hom.: 225 Cov.: 31 AF XY: 0.0433 AC XY: 3223 AN XY: 74448

Gnomad4 AFR AF: 0.00994

Gnomad4 AMR AF: 0.0390

Gnomad4 ASJ AF: 0.0832

Gnomad4 EAS AF: 0.0665

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0566

Gnomad4 NFE AF: 0.0632

Gnomad4 OTH AF: 0.0563

Alfa AF: 0.0523 Hom.: 97

Bravo AF: 0.0423

Asia WGS AF: 0.0400 AC: 140 AN: 3478

EpiCase AF: 0.0601

EpiControl AF: 0.0607

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.5
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800947; hg19: chr1-159683438; COSMIC: COSV99660461;