rs77832441

Positions:

• chr1-159714024-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000255030.9(CRP):​c.176C>T​(p.Thr59Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,613,472 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (13 hom.)
• Consequence: CRP ENST00000255030.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 1.87

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023296297).
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRP	NM_000567.3	c.176C>T	p.Thr59Met	missense_variant	2/2	ENST00000255030.9	NP_000558.2
CRP	NM_001329057.2	c.176C>T	p.Thr59Met	missense_variant	2/3		NP_001315986.1
CRP	NM_001382703.1	c.176C>T	p.Thr59Met	missense_variant	2/3		NP_001369632.1
CRP	NM_001329058.2	c.176C>T	p.Thr59Met	missense_variant	2/4		NP_001315987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRP	ENST00000255030.9	c.176C>T	p.Thr59Met	missense_variant	2/2	1	NM_000567.3	ENSP00000255030	P1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152004 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00145 AC: 363 AN: 250722 Hom.: 0 AF XY: 0.00142 AC XY: 193 AN XY: 135606

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.000376

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00277 AC: 4041 AN: 1461350 Hom.: 13 Cov.: 31 AF XY: 0.00260 AC XY: 1892 AN XY: 727016

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.000529

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152122 Hom.: 1 Cov.: 31 AF XY: 0.00129 AC XY: 96 AN XY: 74338

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00279 Hom.: 1

Bravo AF: 0.00180

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00151 AC: 183

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00279

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

CRP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;T;T
Eigen	Benign	0.024
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T;T;.;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.47
MVP		0.65
MPC		0.20
ClinPred		0.10	T
GERP RS		2.0
Varity_R		0.90
gMVP		0.69

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

LitVar

Other links and lift over

dbSNP: rs77832441; hg19: chr1-159683814;