1-159713734-C-T

Variant names:

• chr1-159713734-C-T
• rs748954737
• NM_000567.3:c.466G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000567.3(CRP):​c.466G>A​(p.Glu156Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRP NM_000567.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.65

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CRP_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRP	NM_000567.3	c.466G>A	p.Glu156Lys	missense_variant	Exon 2 of 2	ENST00000255030.9	NP_000558.2
CRP	NM_001329057.2	c.466G>A	p.Glu156Lys	missense_variant	Exon 2 of 3		NP_001315986.1
CRP	NM_001382703.1	c.194-94G>A		intron_variant	Intron 2 of 2		NP_001369632.1
CRP	NM_001329058.2	c.198-131G>A		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.466G>A	p.Glu156Lys	missense_variant	Exon 2 of 2	1	NM_000567.3	ENSP00000255030.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251468 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.466G>A (p.E156K) alteration is located in exon 2 (coding exon 2) of the CRP gene. This alteration results from a G to A substitution at nucleotide position 466, causing the glutamic acid (E) at amino acid position 156 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.27
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.85		Gain of ubiquitination at E156 (P = 0.0104);
MVP		0.47
MPC		0.23
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.82
gMVP		0.86

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: rs748954737; hg19: chr1-159683524;