rs77832441

Variant names:

• chr1-159714024-G-A
• rs77832441
• NM_000567.3:c.176C>T
• CRP p.Thr59Met

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000567.3(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. 14/22 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 NM_000567.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1
• Conservation: PhyloP100: 1.87
• Publications: 16 publications found

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]

ENSG00000297913 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000567.3. 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
	CRP	NM_000567.3	MANE Select	c.176C>T	p.Thr59Met	missense	Exon 2 of 2	NP_000558.2	P02741-1
	CRP	NM_001329057.2		c.176C>T	p.Thr59Met	missense	Exon 2 of 3	NP_001315986.1	P02741-1
	CRP	NM_001382703.1		c.176C>T	p.Thr59Met	missense	Exon 2 of 3	NP_001369632.1	Q5VVP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRP	ENST00000255030.9	TSL:1 MANE Select	c.176C>T	p.Thr59Met	missense	Exon 2 of 2	ENSP00000255030.5	P02741-1
	CRP	ENST00000437342.1	TSL:1	c.-307-52C>T		intron	N/A	ENSP00000402788.1	C9JRE9
	CRP	ENST00000368110.1	TSL:3	c.176C>T	p.Thr59Met	missense	Exon 2 of 4	ENSP00000357091.1	Q5VVP7

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

GnomAD2 exomes AF: 0.00145 AC: 363 AN: 250722 AF XY: 0.00142

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 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

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86258

European-Finnish (FIN) AF: 0.000529 AC: 28 AN: 52886

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00339 AC: 3775 AN: 1112010

Other (OTH) AF: 0.00195 AC: 118 AN: 60388

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

African (AFR) AF: 0.000385 AC: 16 AN: 41512

American (AMR) AF: 0.00157 AC: 24 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68000

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

Alfa AF: 0.00275 Hom.: 1

Bravo AF: 0.00180

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	CRP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.024
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.9
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Varity_R		0.90
gMVP		0.69
Mutation Taster		=81/19	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77832441;

hg19: chr1-159683814;